Pyralopyridines, process for their preparation and use as therapeutic compounds

ABSTRACT

The present invention provides compounds of formula (I): wherein all variables are as defined herein, pharmaceutical compositions containing the same, processes for preparing the same and their use as pharmaceutical agents.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a 371 Application of PCT/US02/08524, filed 20 Mar.2002, which claims priority to U.S. Application Ser. No. 60/280,047,filed 30 Mar. 2001, U.S. Application Ser. No. 60/307,189, filed 23 Jul.2001, U.S. Application Ser. No. 60/307,786, filed 25 Jul. 2001 and60/315,090 filed 27 Aug. 2001.

BACKGROUND OF THE INVENTION

The present invention relates to novel compounds, pharmaceuticalformulations comprising these compounds, and the use of these compoundsin therapy. More particularly, the present invention relates tocompounds for the prophylaxis and treatment of herpes viral infections.

Of the DNA viruses, those of the herpes group are the sources of themost common viral illnesses in man. The group includes herpes simplexvirus types 1 and 2 (HSV), varicella zoster virus (VZV), cytomegalovirus(CMV), Epstein-Barr virus (EBV), human herpes virus type 6 (HHV-6),human herpes virus type 7 (HHV-7) and human herpes virus type 8 (HHV-8).HSV-1 and HSV-2 are some of the most common infectious agents of man.Most of these viruses are able to persist in the host's neural cells;once infected, individuals are at risk of recurrent clinicalmanifestations of infection which can be both physically andpsychologically distressing.

Herpes simplex viruses (HSV-1 and -2) are the causative agents of herpeslabialis and genital herpes. HSV infection is often characterised byextensive and debilitating lesions of the skin, mouth and/or genitals.Primary infections may be subclinical although tend to be more severethan infections in individuals previously exposed to the virus. Ocularinfection by HSV can lead to keratitis or cataracts thereby endangeringthe host's sight Infection in the new-born, in immunocompromisedpatients or penetration of the infection into the central nervous systemcan prove fatal. In the US alone, 40 million individuals are infectedwith HSV-2, a number that is expected to increase to 60 million by 2007.Over 80% of individuals infected with HSV-2 are unaware they carry andspread the virus, and of those diagnosed less than 20% received oraltherapies. The net result is that less than 5% of the infectedpopulation are treated. Likewise of the 530 million individualsworldwide who carry HSV-1, 81% of the symptomatic population remainuntreated. No cure exists for HSV infection, and once infected,individuals carry the virus for life in a dormant state. Reactivation ofthe virus from latency occurs periodically and may be triggered bystress, environmental factors, and/or suppression of the host immunesystem. Currently, the use of nucleoside analogs such as valaciclovir(VALTREX®) and aciclovir (ZOVIRAX®) is the standard of care for managinggenital herpes virus outbreaks.

Varicella zoster virus (VZV) (also known as herpes zoster virus) is aherpes virus which causes chickenpox and shingles. Chickenpox is theprimary disease produced in a host without immunity, and in youngchildren is usually a mild illness characterised by a vesicular rash andfever. Shingles or zoster is the recurrent form of the disease whichoccurs in adults who were previously infected with VZV. The clinicalmanifestations of shingles are characterised by neuralgia and avesicular skin rash that is unilateral and dermatomal in distribution.Spread of inflammation may lead to paralysis or convulsions. Coma canoccur if the meninges become affected. VZV is of serious concern inpatients receiving immunosuppressive drugs for transplant purposes orfor treatment of malignant neoplasia and is a serious complication ofAIDS patients due to their impaired immune system.

In common with other herpes viruses, infection with CMV leads to alifelong association of virus and host. Congenital infection followinginfection of the mother during pregnancy may give rise to clinicaleffects such as death or gross disease (microcephaly,hepatosplenomegaly, jaundice, mental retardation), retinitis leading toblindness or, in less severe forms, failure to thrive, andsusceptibility to chest and ear infections. CMV infection in patientswho are immunocompromised for example as a result of malignancy,treatment with immunosuppressive drugs following transplantation orinfection with Human Immunodeficiency Virus, may give rise to retinitis,pneumonitis, gastrointestinal disorders and neurological diseases. CMVinfection is also associated with cardiovascular diseases and conditionsincluding restenosis and atherosclerosis.

The main disease caused by EBV is acute or chronic infectiousmononucleosis (glandular fever). Examples of other EBV or EBV associateddiseases include lymphoproliferative disease which frequently occurs inpersons with congenital or acquired cellular immune deficiency, X-linkedlymphoproliferative disease which occurs namely in young boys,EBV-associated B-cell tumours, Hodgkin's disease, nasopharyngealcarcinoma, Burkitt lymphoma, non-Hodgkin's lymphoma, thymomas and oralhairy leukoplakia. EBV infections have also been found in associationwith a variety of epithelial-cell-derived tumours of the upper and lowerrespiratory tracts including the lung. EBV infection has also beenassociated with other diseases and conditions including chronic fatiguesyndrome, multiple sclerosis and Alzheimer's disease.

HHV-6 has been shown to be a causative agent of infantum subitum inchildren and of kidney rejection and interstitial pneumonia in kidneyand bone marrow transplant patients, respectively, and may be associatedwith other diseases such as multiple sclerosis. There is also evidenceof repression of stem cell counts in bone marrow transplant patients.HHV-7 is of undetermined disease aetiology.

Hepatitis B virus (HBV) is a viral pathogen of world-wide majorimportance. The virus is aetiologically associated with primaryhepatocellular carcinoma and is thought to cause 80% of the world'sliver cancer. Clinical effects of infection with HBV range fromheadache, fever, malaise, nausea, vomiting, anorexia and abdominalpains. Replication of the virus is usually controlled by the immuneresponse, with a course of recovery lasting weeks or months in humans,but infection may be more severe leading to persistent chronic liverdisease outlined above.

U.S. Pat. No. 5,498,774 and European Patent No. 0 404 190 to Mitsuderaet al., relates to condensed heterocyclic compounds of the generalformula (I):

wherein Q is a condensed heterocyclic group having a nitrogen atom inthe bridgehead which is unsubstituted or substituted, X is a hydrogenatom or a group attached through C, O, S or N, and Y is an electronattractive group; or its salt which is useful as an agriculturalchemical.

BRIEF SUMMARY OF THE INVENTION

According to a first aspect of the invention there is provided acompound of formula (I):

wherein:

-   R¹ is selected from the group consisting of alkyl, alkenyl, alkynyl,    cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —OR⁷,    —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰ Het, —R¹⁰R⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,    —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het, —R¹⁰OC(O)R⁹, —R¹⁰OC(O)Ay,    —R¹⁰OC(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay,    —C(O)NHR¹⁰Ay, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —R¹⁰C(N H)NR⁹R¹¹,    —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹,    —R¹⁰S(O)_(n)R⁹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹, —S(O)_(n)R⁹, —S(O)_(n)Ay,    —S(O)_(n)Het, cyano, azido and nitro;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —R¹⁰cycloalkyl, —OR⁹, —R¹⁰OR⁹,        —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹, —C(O)R⁹, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁹R¹¹,        —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,        —R¹⁰C(NH)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂NR⁹R¹¹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰NHSO₂R⁹, —SO₂R¹⁰, —R¹⁰SO₂R¹⁰, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   Ay is an aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;    -   n is 0, 1 or 2;-   R² is selected from the group consisting of H, halo, alkyl,    cycloalkyl, alkenyl, cycloalkenyl, —NR⁷R⁸, Ay, —NHR¹⁰Ay, —OR⁷, —OAy,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet,    —NHR¹⁰Het, —OHet and —OR¹⁰Het;-   Y is N or CH;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, cycloalkyl,    alkenyl, Ay, —OR⁷, —OAy, —R¹⁰R⁷, —R¹⁰OAy, —NR⁷R⁸, —NR⁷Ay, —R¹⁰NR⁷R⁸,    —R¹⁰NR⁷Ay, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹, Het, —NHHet    and —NHR¹⁰Het;-   q is 0, 1, 2, 3, 4 or 5;    -   each R⁵ is the same or different and is independently selected        from the group consisting of halo, alkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, Ay, —NHR¹⁰Ay, —NR⁷Ay,        Het, —NHHet, —NHR¹⁰Het, —OR⁷, —OAy, —OHet, —R¹⁰OR⁹, —NR⁷R⁸,        —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het,        —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het,        —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,        —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸,        —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹,        —S(O)_(n)R⁹, cyano, azido and nitro; or    -   two adjacent R⁵ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or aryl;-   p is 0, 1, 2 or 3; and-   each R⁶ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, —R¹⁰cycloalkyl, Ay, Het, —R¹⁰Ay, —R¹⁰Het, —OR⁷, —OAy,    —OHet, —R¹⁰OR⁹, —OR¹⁰Ay, —OR¹⁰Het, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹,    —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸,    —C(O)NR⁷Ay, —C(O)NHR¹⁰Het, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,    —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, azido and nitro; or    -   two adjacent R⁶ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or a 5- or 6-membered heterocyclic        group containing 1 or 2 heteroatoms;-   wherein when Y is CH, R³ is not —NR⁷Ay;    and pharmaceutically acceptable salts, solvates and physiologically    functional derivatives thereof.

In another aspect of the invention there is provided a pharmaceuticalcomposition comprising a compound of formula (I). In one preferredembodiment, the pharmaceutical composition further comprises apharmaceutically acceptable carrier or diluent In one embodiment, thepharmaceutical composition further comprises an antiviral agent selectedfrom the group consisting of aciclovir and valaciclovir.

In a third aspect of the invention, there is provided a method for theprophylaxis or treatment of a herpes viral infection. The methodcomprises administering a therapeutically effective amount of a compoundof formula (I) above or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof. The herpes viralinfection may be selected from the group consisting of herpes simplexvirus 1, herpes simplex virus 2, cytomegalovirus, Epstein Barr virus,varicella zoster virus, human herpes virus 6, human herpes virus 7, andhuman herpes virus 8.

In a fourth aspect, there is provided a method for the treatment orprophylaxis of conditions or diseases associated with a herpes viralinfection in an animal. The method comprises administering to the animala therapeutically effective amount of the compound of formula (I) aboveor a pharmaceutically acceptable salt, solvate or physiologicallyfunctional derivative thereof.

In another aspect, there is provided a process for preparing compoundsof formula (I) wherein Y is N; R² is selected from the group consistingof H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, —NR⁷R⁸, Ay, —NHR¹⁰Ay,—OR⁷, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet,—NHR¹⁰Het, —OHet and —OR¹⁰Het; R³ is H; R⁴ is H and all other variablesare as defined above in connection with compounds of formula (I). Theprocess comprises the steps of: a) reacting a compound of formula (IX):

-   -   wherein R^(1a) is selected from the group consisting of H, halo,        alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay,        —OR¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —C(O)R⁹,        —C(O)Ay, —C(O)Het, —R¹⁰OC(O)R⁹, —R¹⁰C(O)Ay, —R¹⁰OC(O)Het,        —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,        —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,        —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸,        —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹,        —R¹⁰OS(O)_(n)R⁹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹, —S(O)_(n)R⁹,        —S(O)_(n)Ay, —S(O)_(n)Het, cyano, azido and nitro;        with a compound of formula (X)

to prepare a compound of formula (XI):

andb) when R^(1a) is H or halo, converting the compound of formula (XI) toa compound of formula (I).

As another aspect, the present invention provides another process forpreparing compounds of formula (I) wherein Y is N; R² is selected fromthe group consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl,—NR⁷R⁸, Ay, —NHR¹⁰Ay, —OR⁷, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet and —OR¹⁰Het; R³ is selectedfrom the group consisting of H, alkyl, cycloalkyl, alkenyl, Ay, —R¹⁰OR⁷,—R¹⁰OAy, —NR⁷R⁸ where R⁷ and R⁸ are not H, —NR⁷Ay where R⁷ is not H,—R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂AY, —SO₂NHR⁹ andHet; R⁴ is H; and all other variables are as defined above in connectionwith compounds of formula (I). The process comprises the steps of: a)reacting a compound of formula (XV):

-   -   wherein R^(1a) is as defined in the process described above;        with a compound of formula (X) to prepare a compound of formula        (XI), and b) when R^(1a) is H or halo, converting the compound        of formula (XI) to a compound of formula (I).

As another aspect, the present invention provides another process forpreparing compounds of formula (I) wherein Y is N; R² is selected fromthe group consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl,—NR⁷R⁸, Ay, —NHR¹⁰Ay, —OR⁷, —OAy, —S(O)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet and —OR¹⁰Het; and all othervariables are as defined above in connection with compounds of formula(I).

The process comprises the steps of: a) reacting a compound of formula(XVIII):

-   -   wherein R^(1a) is as defined in the process described above;        with a compound of formula (X) followed by oxidative        aromatization, to prepare a compound of formula (XI), and b)        when R^(1a) is H or halo, converting the compound of        formula (XI) to a compound of formula (I).

As another aspect, the present invention provides another process forpreparing compounds of formula (I). The process comprises the steps of:a) reacting a compound of formula (XIX):

-   -   wherein R^(1a) is as defined in the process described above, X¹        is halo and q, R⁵, p    -   and R⁶ are as defined above in connection with compounds of        formula (I); with a compound of formula (XX)

-   -   wherein R², R³, R⁴ and Y are as defined above in connection with        compounds of formula (I) and M² is —B(OH)₂, —B(ORa)₂, —B(Ra)₂,        —Sn(Ra)₃, Zn-halide, ZnRa, Mg-halide where Ra is alkyl or        cycloalkyl and halide is halo,        to prepare a compound of formula (XI), and b) when R^(1a) is H        or halo, converting the compound of formula (XI) to a compound        of formula (I).

The present invention also provides processes for converting a compoundof formula (XI) to a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof; processes for convertinga compound of formula (XI) or a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof to anothercompound of formula (XI) or a pharmaceutically acceptable salt, solvateor physiologically functional derivative thereof; processes forconverting a compound of formula (I) to a pharmaceutically acceptablesalt, solvate or physiologically functional derivative thereof; andprocesses for converting a compound of formula (I) or a pharmaceuticallyacceptable salt, solvate or physiologically functional derivativethereof to another compound of formula (I) or a pharmaceuticallyacceptable salt, solvate or physiologically functional derivativethereof.

In another aspect, the present invention provides a radiolabeledcompound of formula (I) or a pharmaceutically acceptable salt, solvateor physiologically functional derivative thereof. In one embodiment, thepresent invention provides a tritiated compound of formula (I) or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof. In another embodiment, the present inventionprovides a biotinylated compound of formula (I) or a pharmaceuticallyacceptable salt, solvate or physiologically functional derivativethereof.

In another aspect, the present invention provides a compound of formula(I) for use in therapy.

In yet another aspect, the present invention provides a compound offormula (I) for use in the prophylaxis or treatment of a herpes viralinfection.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I), for use in theprophylaxis or treatment of a herpes viral infections in an animal,preferably a human.

In yet another aspect, the present invention provides a compound offormula (I) for use in the prophylaxis or treatment of conditions ordiseases associated with a herpes viral infection in an animal.

In yet another aspect, the present invention provides a pharmacueticalcomposition for use in the prophylaxis or treatment of conditions ordiseases associated with a herpes viral infection in an animal,comprising a compound of formula (I).

In yet another aspect, the present invention provides the use of acompound of formula (I) for the preparation of a medicament for theprophylaxis or treatment of a herpes viral infection in an animal,preferably a human.

In yet another aspect, the present invention provides the use of acompound of formula (I) for the preparation of a medicament for thetreatment or prophylaxis of diseases or conditions associated with aherpes viral infection in an animal, preferably a human. The herpesviral infection may be herpes simplex virus 1, herpes simplex virus 2,cytomegalovirus, Epstein Barr virus, varicella zoster virus, humanherpes virus 6, human herpes virus 7, or human herpes virus 8.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “a compound of the invention” or “a compound of formula(I)” means a compound of formula (I) or a pharmaceutically acceptablesalt, solvate, or physiologically functional derivative thereof.Similarly, with respect to isolatable intermediates such as for example,compounds of formula (IX), the phrase “a compound of formula (number)”means a compound of that formula and pharmaceutically acceptable salts,solvates and physiologically functional derivatives thereof.

As used herein, the terms “alkyl” and “alkylene” refer to straight orbranched hydrocarbon chains containing from 1 to 8 carbon atoms.Examples of “alkyl” as used herein include, but are not limited to,methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl andtert-butyl. Examples of “alkylene” as used herein include, but are notlimited to, methylene, ethylene, propylene, butylene and isobutylene.“Alkyl” and “alkylene” also includes substituted alkyl and substitutedalkylene. The alkyl (alkylene) groups may be optionally substituted withone or more substituents selected from the group consisting of mercapto,nitro, cyano, azido and halo. Perhaloalkyl, such as trifluoromethyl isone particularly preferred alkyl group.

As used herein, the term “cycloalkyl” refers to a non-aromaticcarbocyclic ring having from 3 to 8 carbon atoms and no carbon-carbondouble bonds. “Cycloalkyl” includes by way of example cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.“Cycloalkyl” also includes substituted cycloalkyl. The cycloalkyl mayoptionally be substituted on an available carbon with one or moresubstituents selected from the group consisting of mercapto, nitro,cyano, halo, and alkyl.

As used herein, the term “alkenyl” refers to straight or branchedhydrocarbon chains containing from 2 to 8 carbon atoms and at least oneand up to three carbon-carbon double bonds. Examples of “alkenyl” asused herein include, but are not limited to ethenyl and propenyl.“Alkenyl” also includes substituted alkenyl. The alkenyl groups mayoptionally be substituted on an available carbon with one or moresubstituents selected from the group consisting of mercapto, nitro,cyano, halo and alkyl.

As used herein, the term “cycloalkenyl” refers to a non-aromaticcarbocyclic ring having from 3 to 8 carbon atoms (unless otherwisespecified) and up to 3 carbon-carbon double bonds. “Cycloalkenyl”includes by way of example cyclobutenyl, cyclopentenyl and cyclohexenyl.“Cycloalkenyl” also includes substituted cycloalkenyl. The cycloalkenylmay optionally be substituted on an available carbon with one or moresubstituents selected from the group consisting of mercapto, nitro,cyano, halo, and alkyl.

As used herein, the term “alkynyl” refers to straight or branchedhydrocarbon chains containing from 2 to 8 carbon atoms and at least oneand up to three carbon-carbon triple bonds. Examples of “alkynyl” asused herein include, but are not limited to ethynyl and propynyl.“Alkynyl” also includes substituted alkynyl. The alkynyl groups mayoptionally be substituted on an available carbon with one or moresubstituents selected from the group consistng of mercapto, nitro,cyano, halo and alkyl.

The term “halo” or “halogen” refers to the elements fluorine, chlorine,bromine and iodine.

The term “Ay” refers to monocyclic carbocyclic groups and fused bicycliccarbocyclic groups having from 5 to 12 carbon atoms and having at leastone aromatic ring. Examples of particular aryl groups include but arenot limited to phenyl, and naphthyl. “Aryl” also includes substitutedaryl. Aryl groups may optionally be substituted on an available carbonwith one or more substituents selected from the group consisting ofhalo, alkyl (including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl,alkoxy, cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine,cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano,nitro and azido. Preferred aryl groups according to the inventioninclude but are not limited to phenyl and substituted phenyl.

The term “heterocyclic” (or “heterocycle”) refers to a monocyclicsaturated or unsaturated non-aromatic groups and fused bicyclicnon-aromatic groups, having the specified number of members andcontaining 1, 2, 3 or 4 heteroatoms selected from N, O and S. Examplesof particular heterocyclic groups include but are not limited totetrahydrofuran, dihydropyran, tetrahydropyran, pyran, oxetane,thietane, 1,4-dioxane, 1,3-dioxane, 1,3-dioxalane, piperidine,piperazine, tetrahydropyrimidine, pyrrolidine, morpholine,thiomorpholine, thiazolidine, oxazolidine, tetrahydrothiopyran,tetrahydrothiophene, and the like. “Heterocyclic” also includessubstituted heterocyclic. The heterocyclic group may be optionallysubstituted on an available carbon or heteroatom, with one or moresubstituents selected from the group consisting of halo, alkyl(including perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy,cycloalkoxy, amino, mercapto, hydroxy, alkylhydroxy, alkylamine,cycloalkylamine, carboxy, carboxamide, sulfonamide, Het, amidine, cyano,nitro and azido. Preferred heterocyclic groups according to theinvention include but are not limited to pyrrolidine, piperidineimorpholine, thiomorpholine and piperazine and substituted variantsthereof.

The term “heteroaryl” refers to aromatic monocyclic groups and aromaticfused bicyclic groups having the specified number of members andcontaining 1, 2, 3, or 4 heteroatoms selected from N. O and S. Examplesof particular heteroaryl groups include but are not limited to furan,thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole,oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine,pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran,benzothiophene, indole and indazole. “Heteroaryl” also includessubstituted heteroaryl. The heteroaryl group may optionally besubstituted on an available carbon or heteroatom with one or moresubstituents selected from the group consisting of halo, alkyl(perhaloalkyl), alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy,amino, mercapto, hydroxy, alkylhydroxy, alkylamine, cycloalkylamine,carboxy, carboxamide, sulfonamide, Het, amidine, cyano, nitro and azido.Preferred heteroaryl groups according to the invention include but arenot limited to pyridine, furan, thiophene, pyrrole, imidazole, pyrazole,and pyrimidine, and substituted variants thereof.

The term “members” (or variations thereof such as “membered”) in thecontext of heterocyclic and heteroaryl groups refers to the total atoms,carbon and heteroatoms N, O and/or S, which form the ring. Thus, anexample of a 6-membered heterocyclic ring is piperidine and an exampleof a 6-membered heteroaryl ring is pyridine.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s) thatoccur and events that do not occur.

The present invention provides compounds of formula (I):

wherein:

-   R¹ is selected from the group consisting of alkyl, alkenyl, alkynyl,    cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —OR⁷,    —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,    —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het, —R¹⁰OC(O)R⁹, —R¹⁰OC(O)Ay,    —R¹⁰OC(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay,    —C(O)NHR¹⁰Ay, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —R¹⁰C(NH)NR⁹R¹¹,    —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹,    —R¹⁰OS(O)_(n)R⁹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹, —S(O)_(n)R⁹, —S(O)_(n)Ay,    —S(O)_(n)Het, cyano, azido and nitro;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —R¹⁰cycloalkyl, —OR⁹, —R¹⁰OR⁹,        —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹, —C(O)R⁹, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁹R¹¹,        —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹—R¹⁰NHC(NH)NR⁹R¹¹,        —R¹⁰C(NH)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂NR⁹R¹¹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰NHSO₂R⁹, —SO₂R¹⁰, —R¹⁰SO₂R¹⁰, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)_(w) where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   Ay is an aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;    -   n is 0, 1 or 2;-   R² is selected from the group consisting of H, halo, alkyl,    cycloalkyl, alkenyl, cycloalkenyl, —NR⁷R⁸, Ay, —NHR¹⁰Ay, —OR⁷, —OAy,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet,    —NHR¹⁰Het, —OHet and —OR¹⁰Het;-   Y is N or CH;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, cycloalkyl,    alkenyl, Ay, —OR⁷, —OAy, —R¹⁰OR⁷, —R¹⁰OAy, —NR⁷R⁸, —NR⁷Ay,    —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹,    Het, —NHHet and —NHR¹⁰Het;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, —R¹⁰cycloalkyl, Ay, —NHR¹⁰Ay, —NR⁷Ay, Het, —NHHet,    —NHR¹⁰Het, —OR⁷, —OAy, —OHet, —R¹⁰OR⁹, —NR⁷R⁸, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,    —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,    —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, azido and nitro; or    two adjacent R⁵ groups together with the atoms to which they are    bonded form a C₅₋₆ cycloalkyl or aryl;-   p is 0, 1, 2 or 3; and-   each R⁶ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, —R¹⁰cycloalkyl, Ay, Het, —R¹⁰Ay, —R¹⁰Het, —OR⁷, —OAy,    —OHet, —R¹⁰OR⁹, —OR¹⁰Ay, —OR¹⁰Het, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹,    —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸,    —C(O)NR⁷Ay, —C(O)NHR¹⁰Het, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,    —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, azido and nitro; or    two adjacent R⁶ groups together with the atoms to which they are    bonded form a C₅₋₆ cycloalkyl or a 5- or 6-membered heterocyclic    group containing 1 or 2 heteroatoms;    and pharmaceutically acceptable salts, solvates and physiologically    functional derivatives thereof.

In one preferred class of compounds of formula (I), Y is CH. In anotherpreferred class of compounds of formula (I), Y is N.

Compounds of formula (I) include those compounds wherein R¹ contains anaryl, heterocyclic or heteroaryl moiety. The groups —R¹⁰Ay, —R¹⁰Het,—OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —R¹⁰NR⁷Ay, —C(O)Ay, —C(O)Het,—R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay, —C(NH)NR⁷Ay,—SO₂NR⁷Ay, —S(O)_(n)Ay and —S(O)_(n)Het are examples of groupscontaining an aryl, heterocyclic or heteroaryl moiety. In oneembodiment, compounds of the present invention includes those compoundsdefined wherein R¹ does not contain a heterocyclic or heteroaryl moeity.

Preferably, each R¹ is the same or different and is independentlyselected from the group consisting of alkyl, cycloalkyl, —R¹⁰cycloalkyl,—OR⁷, —OAy, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸,—S(O)₂NR⁷R⁸, —S(O)_(n)R⁹, cyano, nitro and azido, or any subset thereof.

More preferably, each R¹ is the same or different and is independentlyselected from the group consisting of alkyl, —OR⁷, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸,—C(O)NR⁷R⁸ and —S(O)_(n)R⁹, or any subset thereof. The variable n ispreferably O.

In one preferred embodiment, each R¹ is the same or different and isindependently selected form the group consisting of alkyl, —OR⁷,—C(O)NR⁷R⁸ and S(O)_(n)R⁹.

In one preferred embodiment, the compounds of formula (I) are definedwherein when Y is —CH and R¹ is —CO₂R⁹, R⁹ is not H. In anotherpreferred embodiment, the compounds of formula (I) are defined whereinwhen R¹ is —CONR⁷R⁸ neither R⁷ nor R⁸ is H.

In another embodiment, R¹ is selected from the group consisting ofalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl,—R¹⁰Ay, —R¹⁰Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —R¹⁰OR⁹,—R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het,—R¹⁰OC(O)R⁹, —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —CO₂R¹⁰, —R¹⁰CO₂R⁹, —C(O)NR⁷Ay,—C(O)NHR¹⁰Ay, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —R¹⁰C(NH)NR⁹R¹¹,—S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹,—R¹⁰OS(O)_(n)R⁹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹, —S(O)_(n)R⁹, —S(O)_(n)Ay,—S(O)_(n)Het, cyano, azido and nitro, or any subset thereof.

Specific examples of some prefered R¹ groups are selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,thiomethoxy and thioethoxy or any subset thereof.

In one embodiment, compounds of formula (I) are defined where R²contains an aryl, heterocyclic or heteroaryl moiety (e.g., R² isselected from the group consisting of —OAy, Ay, —NHR¹⁰Ay, —S(O)_(n)Ay,—R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het, or any subsetthereof). In another embodiment, compounds of formula (I) are definedwhere R² contains a heterocyclic or heteroaryl moiety (e.g., R² isselected from the group consisting of Het, —NHHet, —NHR¹⁰Het, —OHet and—OR¹⁰Het, or any subset thereof). In yet another embodiment, thecompounds of formula (I) are defined where R² contains no aryl,heterocyclic or heteroaryl moiety (e.g., R² is selected from the groupconsisting of H, halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, —NR⁷R⁸,—OR⁷, —S(O)_(n)R⁹ and —R¹⁰NR⁷R⁸, or any subset thereof). In anotherembodiment, R² contains no heteroaryl or heterocyclic moiety but maycontain an aryl moeity (e.g., R² is selected from the group consistingof H, halo, alkyl, cycloalkyl, alkenyl, cycloalkenyl, —NR⁷R⁸, —OR⁷, Ay,—NHR¹⁰Ay, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, and —R¹⁰NR⁷Ay, orany subset thereof).

In one embodiment the compounds of formula (I) are defined wherein R² isselected from the group consisting of halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, —NR⁷R⁸, —OR⁷, —OAy, —S(O)_(n)R⁹, —R¹⁰NR⁷R⁸, Ay, —R¹⁰NR⁷Ay,Het, —NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het.

R² is preferably selected from the group consisting of —NR⁷R⁸, —OR⁷,—S(O)_(n)R⁹, Het, —NHHet and —NHR¹⁰Het, or any subset thereof. Morepreferably, R² is selected from the group consisting of —NR⁷R⁸, Het,—NHR¹⁰Het and —NHHet, or any subset thereof. Particularly preferredcompounds of formula (I) are defined where R² is —NR⁷R⁸ or Het.

In one embodiment, when Y is CH, R² is not H.

Preferably, R⁷ and R⁸ are each the same or different and areindependently selected from the group consisting of H, alkyl,cycloalkyl, —R¹⁰-cycloalkyl, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹—C(O)R⁹ and —R¹⁰CO₂R⁹,or any subset thereof. More preferably, R⁷ and R⁸ are each the same ordifferent and are independently selected from the group consisting of H,alkyl, cycloalkyl and —R¹⁰-cycloalkyl, or any subset thereof. In oneembodiment, R⁷ and R⁸ are each the same or different and areindependently selected from the group consisting of H, alkyl andcycloalkyl, or any subset thereof.

Preferably R⁹ and R¹¹ are each the same or different and areindependently selected from the group consisting of H, alkyl, cycloalkyland —R¹⁰-cycloalkyl, or any subset thereof. More preferably, R⁹ and R¹¹are each the same or different and are independently selected from thegroup consisting of H and alkyl, or any subset thereof.

Preferably R¹⁰ is alkyl or cycloalkyl; more preferably alkyl.

More particularly, preferred embodiments of the present inventioninclude compounds of formula (I) wherein R² is selected from the groupconsisting of —NH₂, —NH-alkyl, —NH-cycloalkyl, —N(alkyl)(alkyl), -Het(e.g., pyrrolidone), —NHHet and —NH-alkyl-Het, or any subset thereof.More preferably, the compounds of formula (I) are defined wherein R² isselected from the group consisting of —NH-alkyl and —NH-cycloalkyl.Preferred embodiments include those compounds of formula (I) wherein R²is —NH-propyl, —NH-isopropyl, —NH-cyclopropyl, —NH-butyl, —NH-isobutyl,—NH-cyclobutyl, —NH-cyclopentyl, —NH-cyclohexyl, —NH(CH₂)₂OCH₃,pyrrolidine (e.g., pyrrolidine bonded through N) and morpholine (e.g.,morpholine bonded through N), or any subset thereof.

In another embodiment, the compounds of formula (I) include thosecompounds defined where at least one of R³ and R⁴ contains an aryl,heterocyclic or heteroaryl moiety (or more preferably a heterocyclic orheteroaryl moiety but exclude aryl moeities). A preferred embodimentincludes those compounds of formula (I) where neither R³ nor R⁴ containan aryl, heterocyclic or heteroaryl moiety (or more preferably, neithercontains a heterocyclic or heteroaryl moeity but may contain an arylmoiety). Based on the guidance given above for R¹ and R², one skilled inthe art can readily determine the list of appropriate groups defining R³and R⁴ which contain or exclude aryl, heterocyclic or heteroarylmoeities.

R³ is preferably selected from the group consisting of H, halo, alkyl,Ay, —OR⁷, —R¹⁰OR⁷, —NR⁷R⁸, —R¹⁰NR⁷R⁸ and —CO₂R⁷, or any subset thereof.More preferably, R³ is selected from the group consisting of H, halo,alkyl, —OR⁷ and —NR⁷R⁸, or any subset thereof. Most preferably R³ is Hor alkyl. In one embodiment R³ is H.

R⁴ is preferably H, halo, alkyl, Ay, —OR⁷, —R¹⁰OR⁷, —NR⁷R⁸, —R¹⁰NR⁷R⁸and —CO₂R⁷, or any subset thereof. More preferably, R⁴ is H, halo,alkyl, —OR⁷ and —NR⁷R⁸, or any subset thereof. Most preferably R⁴ is Hor alkyl. In one embodiment R⁴ is H.

Preferably q is 0, 1 or 2. In one embodiment, q is 0. In one preferredembodiment, q is 1. In one embodiment, q is 2 and the two R⁵ groups arebonded to adjacent carbon atoms, and optionally, together with the atomsto which they are bonded, they form a C₅₋₆ cycloalkyl or aryl. Thephrase “two adjacent R⁵ groups” refers to two R⁵ groups, each bonded toadjacent carbon atoms on the phenyl ring. In the embodiment where twoadjacent R⁵ groups together with the atoms to which they are bonded forma cycloalkyl or aryl, q is preferably 2, 3, 4 or 5; more preferably 2.

R⁵ may be in the ortho, meta or para position.

Another class of compounds of formula (I) includes those compoundsdefined wherein at least one R⁵ contains an aryl, heterocyclic orheteroaryl moiety (preferably a heterocyclic or heteroaryl moiety) andtwo adjacent R⁵ groups together with the atoms to which they are bondeddo not form a C₅₋₆ cycloalkyl or aryl. Another class of compounds offormula (I) includes those compounds defined wherein q is 3, 4 or 5, atleast one R⁵ contains an aryl, heterocyclic or heteroaryl moiety(preferably a heterocyclic or heteroaryl moiety) and two adjacent R⁵groups together with the atoms to which they are bonded do form C₅₋₆cycloalkyl or aryl. Another class of compounds of formula (I) includesthose compounds defined where no R⁵ contains an aryl, heterocyclic orheteroaryl moiety (or in one embodiment no R⁵ contains a heterocyclic orheteroaryl moeity) and two adjacent R⁵ groups together with the atoms towhich they are bonded do not form a C₅₋₆ cycloalkyl or aryl. Anotherclass of compounds of formula (I) includes those compounds definedwherein q is 2, 3, 4 or 5, no R⁵ contains an aryl, heterocyclic orheteroaryl moiety (or in one embodiment no R⁵ contains a heterocyclic orheteroaryl moiety) and two adjacent R⁵ groups together with the atoms towhich they are bonded do form a C₅₋₆ cycloalkyl or aryl. Based on theguidance given above for R², one skilled in the art can readilydetermine the list of appropriate groups defining R⁵ which contain orexclude aryl, heterocyclic or heteroaryl moeities.

When two adjacent R⁵ groups together with the atoms to which they arebonded form a C₅₋₆ cycloalkyl or aryl, q is preferably 2, 3, 4 or 5;more preferably 2. In such embodiments, each R⁵ group may be the same ordifferent and is preferably selected from the group consisting of alkyl,and alkenyl. For example, in one embodiment two adjacent R⁵ groups areare alkyl and together with the atoms to which they are bonded, theyform a cycloalkyl group such as:

From this example, additional embodiments, including those where twoadjacent R⁵ groups together with the atoms to which they are bonded forman aryl group can be readily ascertained by those skilled in the art.

In one preferred embodiment, two R⁵ groups together with the atoms towhich they are bonded do not form a C₅₋₆ cycloalkyl or aryl.

Preferably, each R⁵ is the same or different and is independentlyselected from the group consisting of halo, alkyl, alkenyl, —OR⁷,—CO₂R⁹, —NR⁷R⁸, —C(O)NR⁷R⁸, Ay, —OAy, —NR⁷Ay, —NHR¹⁰Ay, —C(O)NR⁷Ay, Het,—S(O)₂NR⁷R⁸, cyano, nitro and azido, or any subset thereof. Morepreferably, each R⁵ is the same or different and is independentlyselected from the group consisting of halo, alkyl, —OR⁷, —NR⁷R⁸,—C(O)NR⁷R⁸, Het, —S(O)₂NR⁷R⁸, cyano and nitro, or any subset thereof.Most preferably, each R⁵ is the same or different and is independentlyselected from the group consisting of halo, alkyl, —OR⁷, —NR⁷R⁸ andcyano, or any subset thereof.

In particular, preferred embodiments of the compounds of formula (I) aredefined where R⁵ is halo (e.g., fluoro or chloro), alkyl (e.g., methyl),O-alkyl (e.g., O-methyl, O-isobutyl, and

O-allyl, cyano, —NH—CH₃, and —N(CH₃)₂, or any subset thereof.

In one preferred class of compounds of formula (I), p is 0, 1 or 2. Morepreferably, p is 0 or 1. In one particular preferred embodiment, p is 1.

R⁶ may be in the 4, 5 or 6 position. In one embodiment, p is 1 and R⁶ isin the C-5 position.

One class of compounds of formula (I) includes those compounds definedwherein at least one R⁶ contains an aryl, heterocyclic or heteroarylmoiety (preferably a heterocyclic or heteroaryl moiety) and two adjacentR⁶ groups together with the atoms to which they are bonded do not form aC₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic group containing 1 or2 heteroatoms. Another class of compounds of formula (I) includes thosecompounds defined wherein p is 3, at least one R⁶ contains an aryl,heterocyclic or heteroaryl moiety (preferably a heterocyclic orheteroaryl moiety) and two adjacent R⁶ groups together with the atoms towhich they are bonded do form a C₅₋₆ cycloalkyl or a 5- or 6-memberedheterocyclic group containing 1 or 2 heteroatoms. A preferred class ofcompounds of formula (I) includes those compounds defined where no R⁶contains an aryl, heterocyclic or heteroaryl moiety (or in oneembodiment no R⁶ contains a heterocyclic or heteroaryl moeity) and twoadjacent R⁶ groups together with the atoms to which they are bonded donot form a C₅₋₆ cycloalkyl or a 5- or 6-membered heterocyclic groupcontaining 1 or 2 heteroatoms. Another class of compounds of formula (I)includes those compounds defined wherein p is 2 or 3, no R⁶ contains anaryl, heterocyclic or heteroaryl moiety (or in one embodiment no R⁶contains a heterocyclic or heteroaryl moiety) and two adjacent R⁶ groupstogether with the atoms to which they are bonded do form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic group containing 1 or 2heteroatoms.

Based on the guidance given above for R¹ and R², one skilled in the artcan readily determine the list of appropriate groups defining R⁶ whichcontain or exclude aryl, heterocyclic or heteroaryl moeities.

In those embodiments where two adjacent R⁶ groups together with theatoms to which they are bonded form a C₅₋₆ cycloalkyl or a 5- or6-membered heterocyclic group having 1 or 2 heteroatoms (i.e., acycloalkyl or heterocyclic ring), each R⁶ may be the same or differentand is preferably selected from the group consisting of alkyl, alkenyl,—OR⁷, —NR⁷R⁸ and —S(O)_(n)R⁹. For example, in one embodiment twoadjacent R⁶ groups are —OR⁷ and together with the atoms to which theyare bonded, they form a heterocyclic group such as:

In another embodiment, two adjacent R⁶ groups are alkyl and togetherwith the atoms to which they are bonded, they form a cycloalkyl groupsuch as:

In another embodiment two adjacent R⁶ groups are defined as —OR⁷, —NR⁷R⁸respectively and together with the atoms to which they are bonded, theyform a heterocyclic group such as:

From these examples, additional embodiments can be readily ascertainedby those skilled in the art. In one preferred embodiment, two R⁶ groupstogether with the atoms to which they are bonded do not form a C₅₋₆cycloalkyl or a 5- or 6-membered heterocyclic group.

Preferably, each R⁶ is the same or different and is independentlyselected from the group consisting of halo, alkyl, Ay, Het, —OR⁷, —OAy,—OHet, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay,—C(O)NHR¹⁰Het, —R¹⁰C(O)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —R¹⁰SO₂NHCOR⁹, —S(O)_(n)R⁹,cyano, azido and nitro, or any subset thereof. More preferably, each R⁶is the same or different and is independently selected from the groupconsisting of halo, alkyl, Het, —OR⁷, —C(O)NR⁷R⁸—S(O)₂NR⁷R⁸, —S(O)_(n)R⁹and cyano, or any subset thereof. Most preferably, each R⁶ is the sameor different and is independently selected from the group consisting ofhalo, Het, —OR⁷ and —S(O)_(n)R⁹, or any subset thereof.

In one preferred embodiment, the compounds of formula (I) are definedwherein when Y is —CH and R⁶ is —CO₂R⁹, R⁹ is not H. In anotherpreferred embodiment, the compounds of formula (I) are defined whereinwhen R⁶ is —CONR⁷R⁸, neither R⁷ nor R⁸ is H.

In another embodiment, R⁶ is selected from the group consisting of halo,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, Ay,Het, —R¹⁰Ay, —R¹⁰Het, —OR⁷, —OAy, OHet, —R¹⁰OR⁹, —OR¹⁰Ay, —OR¹⁰Het,—R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R¹⁰,—R¹⁰CO₂R⁹, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,—R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,—R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹,—R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, azido and nitro, or any subset thereof;or two adjacent R⁶ groups together with the atoms to which they arebonded form a C₅₋₆ cycloalkyl or a 5- or 6-membered heterocyclic groupcontaining 1 or 2 heteroatoms.

In one preferred embodiment, R⁶ is selected from the group consisting ofCl, Br, F, methyl, ethyl, isopropyl, pyrrolidine, morpholine, —OH,—O-alkyl, —CONH₂, —CONH-alkyl, —CON(alkyl)₂, —S-alkyl, —CF₃ and —SO₂NH₂,or any subset thereof. In one preferred embodiment, R⁶ is selected fromthe group consisting of Cl, Br, F, methyl, ethyl, isopropyl,pyrrolidine, morpholine, —OH, —O-methyl, —O-isopropyl, —CONH₂,—CON(H)CH₃, —CON(CH₃)₂, —S-methyl, —S-ethyl, —S-isopropyl, —CF₃ and—SO₂NH₂, or any subset thereof. In one preferred embodiment, R⁶ is halo,preferably Cl or Br. In one embodiment R⁶ is trifluoromethyl.

It is to be understood that the present invention includes allcombinations and subsets of the particular and preferred groups definedhereinabove.

Preferred compounds of formula (I) include but are not limited to:

-   2-(4-Fluorophenyl)-7-methyl-3-(4-pyrimidinyl)pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-7-methylthio-3-(4-pyrimidinyl)pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-7-methylsulfinyl-3-(4-pyrimidinyl)pyrazolo[1,5-a]-pyridine;-   7-(2-Fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-pyrazolo[1,5-α]pyridine;-   N-Butyl-4-[7-(2-fluoroethoxy)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   N-Benzyl-4-[7-(2-fluoroethoxy)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   2-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-7-(2,2,2-trifluoro-ethoxy)pyrazolo[1,5-a]pyridine;-   N-Butyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   N-Benzyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]-pyridin-3-yl]-2-pyrimidinamine;-   N-Cyclopropyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   N-Cyclohexyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   3-(4-[2-(4-Fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinylamino)-1-propanol;-   2-(4-Fluorophenyl)-3-(4-(2-methyloxy)pyrimidinyl)-7-(2,2,2-trifluoro    ethoxy)pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-3-(4-(2-phenyloxy)pyrimidinyl)-7-(2,2,2-trifluoro    ethoxy)pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-3-(4-(2-(2,2,2-trifluoroethoxy))pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-α]pyridine;-   2-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(ethylsulfinyl)pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-7-(ethylthio)pyrazolo[1,5-a]pyridine;-   Dimethyl    2-(4-fluorophenyl)-3-(4-(2-cyclopropylamino)pyrimidinyl)-7-pyrazolo[1,5-a    ]pyridinylcarboxamide;-   7-(2-Fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)-pyrazolol[1,5-a]pyridine;-   2-(4-Fluorophenyl)-7-methyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyrid ine;-   2-(4-Fluorophenyl)-7-methoxy-3-(4-pyridinyl)pyrazolo[1,5-a]-pyridine;-   2-(4-Fluorophenyl)-3-(2-fluoro-4-pyridinyl)-7-methoxypyrazolo[1,5-a]pyridine;-   N-Butyl-4-[2-(4-fluorophenyl)-7-methoxypyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine;-   N-{4-[5-Chloro-7-(ethylsulfanyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine-   Ethyl    3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylate;-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-α]pyridine-6-carboxylic    acid;-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxamide;-   N-Butyl-4-[7-butyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]2-pyrimidinamine;-   N-Butyl-4-[2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   N-Butyl-4-[2-(4-fluorophenyl)-7-octylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   N-Cyclopropyl-4-[7-ethyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   4-[7-Butoxy-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine;-   4-[5-Chloro-2-(3-chlorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N    -cyclopentyl-2-pyrimidinamine;-   N-cyclopentyl-6-[2-(4fluorophenyl)-7-(methylthio)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-4-amine;-   N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylthio)-5-morpholin-4-ylpyrazolo[1,5-α]pyridin-3-yl]pyrimidin-2-amine;    and-   N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(isopropylthio)-5-morpholin-4yipyrazolo[1,5-α]pyridin-3-yl]pyrimidin-2-amine;    and pharmaceutically acceptable salts, solvates and physiologically    functional derivatives thereof.

It will be appreciated by those skilled in the art that the compounds ofthe present invention may also be utilized in the form of apharmaceutically acceptable salt or solvate thereof. Thepharmaceutically acceptable salts of the compounds of formula (I)include conventional salts formed from pharmaceutically acceptableinorganic or organic acids or bases as well as quaternary ammoniumsalts. More specific examples of suitable acid salts includehydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric,fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic,tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic,naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic,malic, steroic, tannic and the like. Other acids such as oxalic, whilenot in themselves pharmaceutically acceptable, may be useful in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable salts. Morespecific examples of suitable basic salts include sodium, lithium,potassium, magnesium, aluminium, calcium, zinc,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, N-methylglucamine and procaine salts.

The term “solvate” as used herein refers to a complex of variablestoichiometry formed by a solute (a compound of formula (I)) and asolvent. Solvents, by way of example, include water, methanol, ethanol,or acetic acid.

The term “physiologically functional derivative” as used herein refersto any pharmaceutically acceptable derivative of a compound of thepresent invention, for example, an ester or an amide of a compound offormula (I), which upon administration to an animal, particularly amammal, such as a human, is capable of providing (directly orindirectly) a compound of the present ivnention or an active metabolitethereof. See, for example, Burger's Medicinal Chemistry And DrugDiscovery, 5th Edition, Vol 1: Principles And Practice.

Processes for preparing pharmaceutically acceptable salts, solvates andphysiologically functional derivatives of the compounds of formula (I)are conventional in the art. See, e.g., Burger's Medicinal Chemistry AndDrug Discovery 5th Edition, Vol 1: Principles And Practice.

As will be apparent to those skilled in the art, in the processesdescibed below for the preparation of compounds of formula (I), certainintermediates, particularly compounds of formula (XI), may be in theform of pharmaceutically acceptable salts, solvates or physiologicallyfunctional derivatives of the compound. Those terms as applied to anyintermediate employed in the process of preparing compounds of formula(I) have the same meanings as noted above with respect to compounds offormula (I). Processes for preparing pharmaceutically acceptable salts,solvates and physiologically functional derivatives of suchintermediates are known in the art and are analogous to the process forpreparing pharmaceutically acceptable salts, solvates andphysiologically functional derivatives of the compounds of formula (I).

Certain compounds of formula (I) may exist in stereoisomeric forms (e.g.they may contain one or more asymmetric carbon atoms or may exhibitcis-trans isomerism). The individual stereoisomers (enantiomers anddiastereomers) and mixtures of these are included within the scope ofthe present invention. The present invention also covers the individualisomers of the compounds represented by formula (I) as mixtures withisomers thereof in which one or more chiral centers are inverted.Likewise, it is understood that compounds of formula (I) may exist intautomeric forms other than that shown in the formula and these are alsoincluded within the scope of the present invention.

The present invention further provides compounds of formula (I) for usein medical therapy, e.g. in the treatment or prophylaxis, includingsuppression of recurrence of symptoms, of a viral disease in an animal,e.g. a mammal such as a human. The compounds of formula (I) areespecially useful for the treatment or prophylaxis of viral diseasessuch as herpes viral infections. Herpes viral infections include, forexample, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2),cytomegalovirus (CMV), Epstein Barr virus (EBV), Varicella zoster virus(VZV), human herpes virus 6 (HHV-6), human herpes virus 7 (HHV-7), andhuman herpes virus 8 (HHV-8). Thus, the compounds of the invention arealso useful in the treatment or prophylaxis of the symptoms or effectsof herpes virus infections.

The compounds of the invention are useful in the treatment orprophylaxis of conditions or diseases associated with herpes virusinfections, particularly conditions or diseases associated with latentherpes virus infections in an animal, e.g., a mammal such as a human. Byconditions or diseases associated with herpes viral infections is meanta condition or disease, excluding the viral infection per se, whichresults from the presence of the viral infection, such as chronicfatigue syndrome which is associated with EBV and multiple sclerosiswhich ahs been associated with herpes viral infections such as EBV andHHV-6. Further examples of such conditions or diseases are described inthe background section above.

In addition to those conditions and diseases, the compounds of thepresent invention may also be used for the treatment or prophylaxis ofcardiovascular diseases and conditions associated with herpes virusinfections, in particular atherosclerosis, coronary artery disease andrestenosis and specifically restenosis following angioplasty (RFA).Restenosis is the narrowing of the blood vessels which can occur afterinjury to the vessel wall, for example injury caused by balloonangioplasty or other surgical and/or diagnostic techniques, and ischaracterized by excessive proliferation of smooth muscle cells in thewalls of the blood vessel treated. It is thought that in many patientssuffering from restenosis following angioplasty, viral infection,particularly by CMV and/or HHV-6 plays a pivotal role in theproliferation of the smooth muscle cells in the coronary vessel.Restenosis can occur following a number of surgical and/or diagnostictechniques, for example, transplant surgery, vein grafting, coronaryby-pass grafting and, most commonly following angioplasty.

There is evidence from work done both in vitro and in vivo, indicatingthat restenosis is a multifactorial process. Several cytokines andgrowth factors, acting in concert, stimulate the migration andproliferation of vascular smooth muscle cells (SMC) and production ofextracellular matrix material, which accumulate to occlude the bloodvessel. In addition growth suppressors act to inhibit the proliferationof SMC's and production of extracellular matrix material.

In addition, compounds of formula (I) may be useful in the treatment orprophylaxis of hepatitis B or hepatitis C viruses, human papilloma virus(HPV) and HIV.

The present invention provides a method for the treatment or prophylaxisof a viral infection in an animal such as a mammal (e.g., a human),particularly a herpes viral infection, which method comprisesadministering to the animal a therapeutically effective amount of thecompound of formula (I).

As used herein, the term “prophylaxis” refers to the complete preventionof infection, the prevention of occurrence of symptoms in an infectedsubject, the prevention of recurrence of symptoms in an infectedsubject, or a decrease in severity or frequency of symptoms of viralinfection, condition or disease in the subject.

As used herein, the term “treatment” refers to the partial or totalelimination of symptoms or decrease in severity of symptoms of viralinfection, condition or disease in the subject, or the elimination ordecrease of viral presence in the subject.

As used herein, the term “therapeutically effective amount” means anamount of a compound of formula (I) which is sufficient, in the subjectto which it is administered, to treat or prevent the stated disease,condition or infection. For example, a therapeutically effective amountof a compound of formula (I) for the treatment of a herpes virusinfection is an amount sufficient to treat the herpes viral infection inthe subject.

The present invention also provides a method for the treatment orprophylaxis of conditions or diseases associated with herpes viralinfections in an animal such as a mammal (e.g., a human), whichcomprises administering to the animal a therapeutically effective amountof the compound of formula (I). In one embodiment, the present inventionprovides a method for the treatment or prophylaxis of chronic fatiguesyndrome and multiple sclerosis in an animal such as a mammal (e.g., ahuman), which comprises administering to the animal a therapeuticallyeffective amount of a compound of formula (I). The foregoing method isparticularly useful for the treatment or prophylaxis of chronic fatiguesyndrome and multiple sclerosis associated with latent infection with aherpes virus.

In another embodiment, the present invention provides a method for thetreatment or prophylaxis of a cardiovascular condition such asatherosclerosis, coronary artery disease or restenosis (particularlyrestenosis followign surgery such as angioplasty), which comprisesadministering to the animal a therapeutically effective antiviral amountof the compound of formula (I).

The present invention further provides a method for the treatment orprophylaxis of hepatitis B or hepatitis C viruses in an animal such as amammal (e.g., a human), which comprises administering to the animal atherapeutically effective amount of the compound of formula (I).

The present invention further provides a method for the treatment orprophylaxis of human papilloma virus in an animal such as a mammal(e.g., a human), which comprises administering to the animal atherapeutically effective amount of the compound of formula (I).

The present invention further provides a method for the treatment orprophylaxis of HIV in an animal such as a mammal (e.g., a human), whichcomprises administering to the animal a therapeutically effective amountof the compound of formula (I).

The present invention also provides the use of the compound of formula(I) in the preparation of a medicament for the treatment or prophylaxisof a viral infection in an animal such as a mammal (e.g., a human),particularly a herpes viral infection; the use of the comound of formula(I) in the preparation of a medicament for the treatment of conditionsor disease associated with a herpes viral infection; and the use of thecompound of formula (I) in the preparation of a medicament for thetreatment or prophylaxis of hepatitis B or hepatitis C viruses, humanpapilloma virus and HIV. In particular, the present invention alsoprovides the use of a compound of formula (I) in the preparation of amedicament for the treatment or prophylaxis of chronic fatigue syndromeor multiple sclerosis. In one embodiment, the present invention providesthe use of a compound of formula (I) in the preparation of a medicamentfor the treatment or prophylaxis of cardiovascular disease, such asrestenosis and atherosclerosis.

The compounds of formula (I) are conveniently administered in the formof pharmaceutical compositions. Such compositions may conveniently bepresented for use in conventional manner in admixture with one or morephysiologically acceptable carriers or diluents.

While it is possible that compounds of the present invention may betherapeutically administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation orcomposition. The pharmaceutical composition may include one or morepharmaceutically acceptable carriers or diluents together with thecompound of formula (I). The carrier(s) or diluent(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

Accordingly, the present invention further provides for a pharmaceuticalformulation or composition comprising a compound of formula (I). In oneembodiment, the pharmaceutical formulation further comprises one or morepharmaceutically acceptable carriers or dilents and, optionally, othertherapeutic and/or prophylactic ingredients.

The formulations include those suitable for oral, parenteral (includingsubcutaneous e.g. by injection or by depot tablet, intradermal,intrathecal, intramuscular e.g. by depot and intravenous), rectal andtopical (including dermal, buccal and sublingual) administrationalthough the most suitable route may depend upon for example thecondition, age, and disorder of the recipient as well as the viralinfection or disease being treated. The formulations may conveniently bepresented in unit dosage form and may be prepared by any of the methodswell known in the art of pharmacy. All methods include the step ofbringing into association the compound(s) (“active ingredient”) with thecarrier which constitutes one or more accessory ingredients. In generalthe formulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation. Formulations suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tablets(e.g. chewable tablets in particular for paediatric administration) eachcontaining a predetermined amount of the active ingredient; as a powderor granules; as a solution or a suspension in an aqueous liquid or anon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste. A tablet may be made bycompression or moulding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with other conventional excipientssuch as binding agents, (for example, syrup, acacia, gelatin, sorbitol,tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (forexample, lactose, sugar, microcrystalline cellulose, maize-starch,calcium phosphate or sorbitol), lubricants (for example, magnesiumstearate, stearic acid, talc, polyethylene glycol or silica),disintegrants (for example, potato starch or sodium starch glycollate)or wetting agents, such as sodium lauryl sulfate. Moulded tablets may bemade by moulding in a suitable machine a mixture of the powderedcompound moistened with an inert liquid diluent. The tablets mayoptionally be coated or scored and may be formulated so as to provideslow or controlled release of the active ingredient therein. The tabletsmay be coated according to methods well-known in the art.

Alternatively, the compounds of the present invention may beincorporated into oral liquid preparations such as aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, for example.Moreover, formulations containing these compounds may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may contain conventional additives such assuspending agents such as sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats;emulsifying agents such as lecithin, sorbitan mono-oleate or acacia;non-aqueous vehicles (which may include edible oils) such as almond oil,fractionated coconut oil, oily esters, propylene glycol or ethylalcohol; and preservatives such as methyl or propyl p-hydroxybenzoatesor sorbic acid. Such preparations may also be formulated assuppositories, e.g., containing conventional suppository bases such ascocoa butter or other glycerides.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations may be presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilised) condition requiring only the addition of asterile liquid carrier, for example, water-for-injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described. Formulations for rectal administration may bepresented as a suppository with the usual carriers such as cocoa butter,hard fat or polyethylene glycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavoured base such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a base such as gelatinand glycerin or sucrose and acacia.

The compounds may also be formulated as depot preparations. Such longacting formulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question, for example thosesuitable for oral administration may include flavouring agents.

It will be appreciated that the amount of a compound of the inventionrequired for use in treatment will vary with the nature of the conditionbeing treated and the age and the condition of the patient and will beultimately at the discretion of the attendant physician or veterinarian.In general, however, doses employed for adult human treatment willtypically be in the range of 0.02–5000 mg per day, preferably 100–1500mg per day. The desired dose may conveniently be presented in a singledose or as divided doses administered at appropriate intervals, forexample as two, three, four or more sub-doses per day. The formulationsaccording to the invention may contain between 0.1–99% of the activeingredient, conveniently from 30–95% for tablets and capsules and 3–50%for liquid preparations.

The compound of formula (I) for use in the instant invention may be usedin combination with other therapeutic agents for example, non-nucleotidereverse transcriptase inhibitors, nucleoside reverse transcriptaseinhibitors, protease inhibitors and/or other antiviral agents. Theinvention thus provides in a further aspect the use of a combinationcomprising a compound of formula (I) with a further therapeutic agent inthe treatment of viral infections. Particular antiviral agents which maybe combined with the compounds of the present invention includeaciclovir, valaciclovir, fameyclovir, ganciclovir, docosanol, miribavir,amprenavir, lamivudine, zidovudine, and abacavir. Preferred antiviralagents for combining with the compounds of the present invention includeaciclovir and valaciclovir. Thus the present invention provides in afurther aspect, a combination comprising a compound of formula (I) andan antiviral agent selected from the group consisting of aciclovir orvalaciclovir; the use of such combination in the treatment of viralinfections and the preparation of a medicament for the treatment ofviral infections, and a method of treating viral infections comprisingadministering a compound of formula (I) and an antiviral agent selectedfrom the group consisting of acyclovir and valacyclovir.

When the compounds of formula (I) are used in combination with othertherapeutic agents, the compounds may be administered eithersequentially or simultaneously by any convenient route.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above optionallytogether with a pharmaceutically acceptable carrier or diluent comprisea further aspect of the invention. The individual components of suchcombinations may be administered either sequentially or simultaneouslyin separate or combined pharmaceutical formulations.

When combined in the same formulation it will be appreciated that thetwo compounds must be stable and compatible with each other and theother components of the formulation and may be formulated foradministration. When formulated separately they may be provided in anyconvenient formulation, in such a manner as are known for such compoundsin the art.

When a compound of formula (I) is used in combination with a secondtherapeutic agent active against the viral infection, the dose of eachcompound may differ from that when the compound is used alone.Appropriate doses will be readily appreciated by those skilled in theart.

Compounds of formula (I) are prepared using the methods described below.The following methods and schemes describe processes for preparingcompounds of formula (XI) and pharmaceutically acceptable salts,solvates and physiologically functional derivatives thereof. It will beappreciated by those skilled in the art that the compounds of formula(XI) encompass all compounds of formula (I) and are in fact the same asthe compounds of formula (I) when compounds of formula (XI) are definedwherein R^(1a)═R¹. When the compounds of formula (XI) are definedwherein R^(1a) is H or halo, the compounds of formula (XI) orpharmaceutically acceptable salts, solvates and physiologicallyfunctional derivatives thereof may be converted into compounds offormula (I) using methods described below.

Compounds of formula (XI) wherein Y is N; R² is selected from the groupconsisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, —NR⁷R⁸, Ay,—NHR¹⁰Ay, —OR⁷, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,Het, —NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het; R³ is H and R⁴ is H, may beconveniently prepared by a general process outlined in Scheme 1 below.

wherein:

-   R^(1a) is selected from the group consisting of H, halo, alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰Ay,    —R¹⁰Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸,    —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het, —R¹⁰OC(O)R⁹,    —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸,    —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,    —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰OS(O)_(n)R⁹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, cyano, azido and nitro;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —R¹⁰cycloalkyl, —OR⁹, —R¹⁰OR⁹,        —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹, —C(O)R⁹, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁹R¹¹,        —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,        —R¹⁰C(NH)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂NR⁹R¹¹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰NHSO₂R⁹, —SO₂R¹⁰, —R¹⁰SO₂R¹⁰, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)w where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   Ay is an aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;    -   n is 0, 1 or 2;-   R² is selected from the group consisting of H, alkyl, cycloalkyl,    alkenyl, cycloalkenyl, —NR⁷R⁸, Ay, —NHR¹⁰Ay, —OR⁷, —OAy,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet,    —NHR¹⁰Het, —OHet and —OR¹⁰Het;-   Y is N;-   R³ and R⁴ are both H;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, —R¹⁰cycloalkyl, Ay, —NHR¹⁰Ay, —NR⁷Ay, Het, —NHHet,    —NHR¹⁰Het, —OR⁷, —OAy, —OHet, —R¹⁰OR⁹, —NR⁷R⁸, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,    —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,    —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, azido and nitro; or    two adjacent R⁵ groups together with the atoms to which they are    bonded form a C₅₋₆ cycloalkyl or aryl;-   p is 0, 1, 2 or 3;-   each R⁶ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, —R¹⁰cycloalkyl, Ay, Het, —R¹⁰Ay, —R¹⁰Het, —OR⁷, —OAy,    —OHet, —R¹⁰R⁹, —OR¹⁰Ay, —OR¹⁰Het, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹,    —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸,    —C(O)NR⁷Ay, —C(O)NHR¹⁰Het, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,    —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, azido and nitro; or    -   two adjacent R⁶ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or a 5- or 6-membered heterocyclic        group containing 1 or 2 heteroatoms; and-   Ra is alkyl or cycloalkyl.

Generally, the process for preparing the compounds of formula (I)wherein Y is N; R² is selected from the group consisting of H, alkyl,cycloalkyl, alkenyl, cycloalkenyl, —NR⁷R⁸, Ay, —NHR¹⁰Ay, —OR⁷, —OAy,—S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het,—OHet, and —OR¹⁰Het; R³ is H and R⁴ is H, (all formulas and all othervariables having been defined above in connection with Scheme 1)comprises the steps of:

-   (a) reacting a 2-picoline compound of formula (III) with a    benzoylating agent of formula (II) to prepare the compound of    formula (IV);-   (b) reacting the compound of formula (IV) with a hydroxylamine    source to prepare a compound of formula (V);-   (c) reacting the compound of formula (V) with an acylating or    sulfonylating agent to prepare a compound of formula (VI);-   (d) rearranging the compound of formula (VI) to prepare a compound    of formula (VII);-   (e) acylating the compound of formula (VII) to prepare a compound of    formula (VIII);-   (f) reacting the compound of formula (VIII) with a dimethylformamide    dialkyl acetal of formula (CH₃)₂NCH(ORa)₂ to prepare a compound of    formula (IX);-   (g) reacting the compound of formula (IX) with a compound of    formula (X) to prepare a compound of formula (XI); and-   (h) when R^(1a) is H or halo, converting the compound of    formula (XI) to a compound of formula (I).

When the compounds of formula (XI) are defined where R^(1a) is H orhalo, the process for preparing compounds of formula (I) comprises theadditional step (h) of converting the compounds of formula (XI) tocompounds of formula (I). Such conversion can be achieved using themethods described below or other suitable methods conventional in theart for this type of transformation.

More specifically, compounds of formula (I) wherein Y is N; R² isselected from the group consisting of H, alkyl, cycloalkyl, alkenyl,cycloalkenyl, —NR⁷R⁸, Ay, —NHR¹⁰Ay, —OR⁷, —OAy, —S(O)_(n)R⁹,—S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet, and—OR¹⁰Het; R¹³ is H and R⁴ is H, can be prepared by reacting a compoundof formula (IX) with a compound of formula (X) to prepare a compound offormula (XI), and when R^(1a)is H or halo, converting to a compound offormula (I).

-   -   wherein all variables are as defined above in connection with        Scheme 1.

This method can be readily carried out by mixing a compound of formula(IX) with a compound of formula (X) in a suitable solvent, optionally inthe presence of a base (preferably when the amidine is in a salt form),and heating the reaction to 50–150° C. Typical solvents include loweralcohols such as methanol, ethanol, isopropanol, dimethylformamide, andthe like. The base is typically a sodium alkoxide, potassium carbonate,or an amine base such as triethylamine. In one embodiment, the solventis dimethylformamide and the base is potassium carbonate, or an aminebase such as triethylamine.

Compounds of the formula (VIII) may be conveniently prepared by reactinga compound of formula (VII) with a dimethylformamide dialkyl acetal offormula (CH₃)₂NCH(ORa)₂.

-   -   wherein all variables are as defined above in connection with        Scheme 1.

Typical dimethylformamide dialkylacetal compounds for use in this methodinclude but are not limited to dimethylformamide dimethylacetal anddimethylformamide di-tert-butylacetal. The reaction is carried out bymixing a compound of formula (VIII) with the dimethylformamide dialkylacetal, optionally with heating.

Compounds of the formula (VIII) may be conveniently prepared fromcompounds of the formula (VII) using an acylation procedure.

-   -   wherein all variables are as defined above in connection with        Scheme 1.

Typically the acylation is carried out by treating the compounds offormula (VII) with an acylating agent, optionally in the presence of anacid or Lewis acid catalyst in an inert solvent with optional heating.Typical acylating agents will be readily determined by those skilled inthe art. One preferred acylating agent is acetic anhydride. Lewis acidcatalysts are also known to those skilled in the art. One preferredLewis acid catalyst for use in this reaction is boron trifluoridediethyl etherate. A suitable solvent is toluene.

Compounds of formula (VII) are conveniently prepared by rearranging anazirine compound of formula (VI).

-   -   wherein all variables are as defined above in connection with        Scheme 1.

The rearrangement of the azirines of formula (VI) can be accomplished byheating a solution of the azirine of formula (VI) in a suitable solventat a temperature of about 160–200° C. Suitable inert solvents include,but are not limited to, 1-methyl-2-pyrrolidinone, and1,2,4-trichlorobenzene. A more preferred method for rearrangement of theazirine of formula (VI) to compounds of formula (VII) involves reactingthe compound of formula (VI) with ferrous chloride (FeCl₂) or ferricchloride (FeCl₃). This reaction is typically done in an inert solventwith heating. A preferred solvent for this reaction is1,2-dimethoxyethane and the like.

Typically the azirines of formula (VI) are prepared from oxime compoundsof formula (V) by treatment with acylating or sulfonylating agents inthe presence of a base.

-   -   wherein all variables are as defined above in connection with        Scheme 1.

Typical acylating or sulfonylating agents include but are not limitedto, acetic anhydride, trifluoroacetic anhydride, methanesulfonylchloride, toluenesulfonyl chloride and the like. Typical bases include,but are not limited to, triethylamine, diisopropylethylamine, pyridine,and the like. The reaction may be carried out in an inert solvent suchas for example, chloroform, dichloromethane, toluene or the like.

The oxime compounds of formula (V) are readily prepared by treatingketone compounds of formula (IV) with a hydroxylamine source, in asuitable solvent, and optionally with a base.

-   -   wherein all variables are as defined above in connection with        Scheme 1.

Preferrably the hydroxylamine is hydroxylamine hydrochloride and thebase is an aqueous solution of sodium hydroxide. Suitable solventsinclude lower alcohols such as methanol, ethanol and isopropanol.

The ketone compounds of formula (IV) can be prepared by treatment of apicoline compound of formula (III) with a benzoylating agent of formula(II) in the presence of a base.

-   -   wherein all variables are as defined above in connection with        Scheme 1.

The benzoylating agents of formula (II) and the picoline compounds offormula (III) are commercially available or may be prepared usingconventional methods known to those skilled in the art. Preferredbenzoylating agents of formula (II) include, but are not limited to,benzoyl esters. An example of a suitable base is lithiumbis(trimethylsilyl)amide in an inert solvent such as tetrahydrofuran.

An alternative synthesis for compounds of formula (VII) involvestreating a ketone of formula (IV) with an aminating agent in a suitablesolvent and optionally heating the reaction. The aminating agent is,preferably, O-(mesitylsulfonyl)hydroxylamine and preferred solventsinclude chloroform, dichloromethane and the like.

-   -   wherein all variables are as defined above in connection with        Scheme 1.

Ketones such as the compounds of formula (IV) can be readily preparedusing procedures described in the literature (Cassity, R. P.; Taylor, LT.; Wolfe, J. F. J.Org. Chem. 1978, 2286) and in concert with thedetails described above in Scheme 1.

Another approach to the synthesis of compounds of formula (VIII)involves the conversion of ketones of formula (IV) to oximes such as (V)followed by treatment of the oximes with an aminating agent.

-   -   wherein all variables are as defined above in connection with        Scheme 1. This reaction may be conducted using essentially the        reaction conditions employed for the foregoing conversion of the        ketone to the compounds of formula (VII).

Preparation of the compounds of formula (V) is described above.

Another alternative synthesis for the compounds of formula (VII)involves the decarboxylation of a compound of formula (XXIII).

-   -   wherein all variables are as described above in connection with        Scheme 1.

The decarboxylation may be carried out by any one of a variety ofmethods described in the literature for similar decarboxylations. Forexample: heating a solution of a compound of formula (XXIII) in an inertsolvent, or conversion to a ‘Barton ester’ followed by treatment with aradical reductant, for example tributyltin hydride (Crich, D.Aldrichimica Acta, 1987, 20, 35).

Compounds of formula (XXIII) can be prepared by simple hydrolysis oflower alkyl esters of formula (XXIV).

-   -   wherein all variables are as defined above in connection with        Scheme 1.

The ester compounds formula (XXIV) can be conveniently hydrolyzed totheir corresponding caboxylic acids (i.e., compounds of formula (XXIII)by standard hydrolysis conditions employed to effect similar hydrolysisreactions (Larock, Comprehensive Organic Transformations, 1989, 981).For example, treatment of a solution of a compound of formula (XXIV) ina lower alcohol, for example methanol, with sodium hydroxide followed byheating the mixture for an appropriate time gives the compound offormula (XXV).

Esters such as compounds of formula (XXIV) may be prepared by a [3+2]dipolar cycloaddition reaction between compounds of formula (XXV) andacetylene compounds of formula (XXVI). See, Hardy, C. R. Adv. Het. Chem.1984, 36, 343.

-   -   wherein X⁺ is a halide ion and all other variables are as        defined above in connection with Scheme 1.

Conveniently the reaction may be carried out by mixing the compound offormula (XXV) and the compound of formula (XXVI) in equal molar amounts,in an inert solvent, and adding a suitable base. The mixture is thenstirred at between 20–100° C. until the reaction is judged complete bythe disappearance of one of the reactants. Preferred solvents includebut are not limited to acetonitrile, dioxane, tetrahydrofuran,dimethylformamide and the like. Preferred bases include non-nucleophilicamines such as 1,8-diazabicyclo[5.4.0]undec-7-ene,1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and thelike.

Compounds of formula (XXV) are aminated pyridine derivatives and areeither commercially available or can be conveniently prepared byreacting a suitable pyridine with an aminating reagent such asO-(mesitylsulfonyl)hydroxylamine, O-(diphenylphosphinyl)hydroxylamineand the like.

Compounds of formula (XXVI) are either known compounds or compoundswhich can be prepared using methods described in the literature.Preferred methods include the reaction of acetylenes such as those offormula (XXVII) with a suitable base to generate an acetylenic anion andsubsequent reaction of the anion with an alkoxycarbonylating agent.

Preferably the compound of formula (XXVII) is dissolved in an inertsolvent, such as tetrahydrofuran, and the solution is cooled to about−75° C. A non-nuclephilic base is added in sufficient quantity to effectdeprotonation of the compound of formula (XXVII). The preferred basesinclude, but are not limited to, n-butyllithium, lithiumdiisopropylamide, sodium bis(trimethylsilyl)amide and the like. To thereaction mixture is then added a reagent capable of reacting with ananion to introduce an alkoxycarbonyl group. Preferred reagents include,but are not limited to, methyl chloroformate, ethyl chloroformate,benzyl chloroformate and the like.

Compounds of formula (XXVII) are either known compounds or can beprepared by literature methods such as those described in, for example,Negishi, E J. Org. Chem. 1997, 62, 8957.

In a further embodiment of the present invention, compounds of formula(XI) wherein Y is N; R² is selected from the group consisting of H,alkyl, cycloalkyl, alkenyl, cycloalkenyl, —NR⁷R⁸, Ay, —NHR¹⁰Ay, —OR⁷,—OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet,—NHR¹⁰Het, —OHet, and —OR¹⁰Het; R³ is selected from the group consistingof H, alkyl, cycloalkyl, alkenyl, Ay, —R¹⁰OR⁷, —R¹⁰OAy, —NR⁷R⁸ where R⁷and R⁸ are not H, —NR⁷Ay where R⁷ is not H, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,—C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹ and Het; and R⁴ is H, andpharmacuetically acceptable salts, solvates and physiologicallyfunctional derivatives thereof, may be conveniently prepared by theprocess outlined in Scheme 2 below.

wherein:

-   R^(1a) is selected from the group consisting of H, halo, alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰Ay,    —R¹⁰Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸,    —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het, —R¹⁰OC(O)R⁹,    —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸,    —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,    —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰OS(O)_(n)R⁹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, cyano, azido and nitro;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —R¹⁰cycloalkyl, —OR⁹, —R¹⁰OR⁹,        —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹, —C(O)R⁹, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁹R¹¹,        —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,        —R¹⁰C(NH)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂NR⁹R¹¹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰NHSO₂R⁹, —SO₂R¹⁰, —R¹⁰SO₂R¹⁰, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)w where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   Ay is an aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;    -   n is ₁ or 2;-   R² is selected from the group consisting of H, alkyl, cycloalkyl,    alkenyl, cycloalkenyl, —NR⁷R⁸, Ay, —NHR¹⁰Ay, —OR⁷, —OAy,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet,    —NHR¹⁰Het, —OHet and —OR¹⁰Het;-   Y is N;-   R³ is selected from the group consisting of H, alkyl, cycloalkyl,    alkenyl, Ay, —R¹⁰OR⁷, —R¹⁰OAy, —NR⁷R⁸ where R⁷ and R⁸ are not H,    —NR⁷Ay where R⁷ is not H, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, C(O)Ay,    —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹ and Het;-   R⁴ is H;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, —R¹⁰cycloalkyl, Ay, —NHR¹⁰Ay, —NR⁷Ay, Het, —NHHet,    —NHR¹⁰Het, —OR⁷, —OAy, —OHet, —R¹⁰OR⁹, —NR⁷R⁸, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,    —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,    —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, azido and nitro; or    two adjacent R⁵ groups together with the atoms to which they are    bonded form a C₅₋₆ cycloalkyl or aryl;-   p is 0, 1, 2 or 3; each R⁶ is the same or different and is    independently selected from the group consisting of halo, alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, Ay, Het,    —R¹⁰Ay, —R¹⁰Het, —OR⁷, —OAy, —OHet, —R¹⁰OR⁹, —OR¹⁰Ay, —OR¹⁰Het,    —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het,    —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het,    —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,    —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,    —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, azido    and nitro; or two adjacent R⁶ groups together with the atoms to    which they are bonded form a C⁵⁻⁶ cycloalkyl or a 5- or 6-membered    heterocyclic group containing 1 or 2 heteroatoms; and-   M¹ is Li, Mg-halide or cerium-halide, wherein halide is halo.

Generally, the process for preparing compounds of formula (I) wherein Yis N; R² is selected from the group consisting of H, alkyl, cycloalkyl,alkenyl, cycloalkenyl, —NR⁷R⁸, Ay, —NHR¹⁰Ay, —OR⁷, —OAy, —S(O)_(n)R⁹,—S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet, and—OR¹⁰Het; R³ is selected from the group consisting of H, alkyl,cycloalkyl, alkenyl, Ay, —R¹⁰OR⁷, —R¹⁰OAy, —NR⁷R⁸ where R⁷ and R⁸ arenot H, —NR⁷Ay where R⁷ is not H, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay,—CO₂R⁷, —CO₂Ay, —SO₂NHR⁹ and Het; and R⁴ is H, (all other variableshaving been defined above in connection with Scheme 2), comprises thefollowing steps:

-   (a) formylating the compound of formula (VII) to prepare a compound    of formula (XII);-   (b) reacting the compound of formula (XII) with a compound of    formula (XIII) to prepare a compound of formula (XIV);-   (c) oxidizing the compound of formula (XI) to prepare a compound of    formula (XV);-   (d) reacting the compound of formula (XV) with a compound of    formula (X) to prepare the compound of formula (XI); and-   (e) when R^(1a) is H or halo, converting the compound of    formula (XI) to a compound of formula (I).

When the compounds of formula (XI) are defined where R^(1a) is H orhalo, the process for preparing compounds of formula (I) comprises theadditional step (e) of converting the compounds of formula (XI) tocompounds of formula (I). Such conversion can be achieved using themethods described below or other suitable methods conventional in theart for this type of transformation.

More specifically, compounds of formula (I) wherein Y is N; R² isselected from the group consisting of H, alkyl, cycloalkyl, alkenyl,cycloalkenyl, —NR⁷R⁶, Ay, —NHR¹⁰Ay, —OR⁷, —OAy, —S(O)_(n)R⁹,—S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet, and—OR¹⁰Het; R³ is selected from the group consisting of H, alkyl,cycloalkyl, alkenyl, Ay, —R¹⁰R⁷, —R¹⁰OAy, —NR⁷R⁸ where R⁷ and R⁸ are notH, —NR⁷Ay where R⁷ is not H, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay,—CO₂R⁷, —CO₂Ay, —SO₂NHR⁹ and Het; and R⁴ is H, may be prepared byreacting a compound of formula (XV) with a compound of formula (X) toprepare a compound of formula (XI), and when R^(1a) is H or halo,converting to a compound of formula (I).

-   -   wherein all variables are as defined above in connection with        Scheme 2.

This method can be readily carried out by mixing a compound of formula(XV) with a compound of formula (X) in a suitable solvent, optionally inthe presence of a base. The reaction may be heated to 50–150° C. orperformed at ambient temperature. Typical solvents include but are notlimited to lower alcohols such as methanol, ethanol, isopropanol and thelike. Typical bases include for example, sodium alkoxide, potassiumcarbonate, or an amine base such as triethylamine. In anotherembodiment, the solvent is N,N-dimethylformamide and the base ispotassium carbonate, or an amine base such as triethylamine.

Compounds of formula (XV) may be conveniently prepared by oxidation of acompound of formula (XI).

wherein all variables are as defined above in connection with Scheme 2.Preferred oxidizing agents include but are not limited to, manganesedioxide, and the like, in an inert solvent. Suitable inert solventsinclude but are not limited to, dichloromethane, chloroform,N,N-dimethylformamide, ether, and the like.

Compounds of formula (XI) may be conveniently prepared by reacting acompound of formula (XII) with a compound of formula (XIII).

wherein all variables are as defined above in connection with Scheme 2.

Preferred metals (M¹) in the compounds of formula (XIII) include but arenot limited to, lithium, magnesium(II) halides, cerium(III) halides, andthe like. Compounds of formula (XIII) may be purchased from commercialsources or prepared by methods known to one skilled in the art.

Compounds of formula (XII) may be conveniently prepared from compoundsof formula (VII) by a formylation procedure.

wherein all variables are as defined above in connection with Scheme 2.

Typically the formylation is carried out via the Vilsmeier-Haackreaction. The Vilsmeier-Haack reagents can be purchased from commercialsources or prepared in situ. Preferable conditions include, but are notlimited to treating compounds of formula (VI) with a premixed solutionof phosphorous oxychloride in N,N-dimethylformamide optionally withheating the reaction to 50–150° C.

The compounds of formula (VII) are prepared according to the processdescribed above in connection with Scheme 1.

Further compounds of formula (XI) wherein Y is N and R² is selected fromthe group consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl,—NR⁷R⁸, Ay, —NHR¹⁰Ay, —OR⁷, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet and —OR¹⁰Het, may beconveniently prepared by the process outlined in Scheme 3 below.

wherein:

-   R^(1a) is selected from the group consisting of H, halo, alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰Ay,    —R¹⁰Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —R¹⁰R⁹, —R¹⁰NR⁷R⁸,    —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het, —R¹⁰OC(O)R⁹,    —R¹⁰C(O)Ay, —R¹⁰OC(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay,    —C(O)NHR¹⁰Ay, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,    —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —R¹⁰C(NH)NR⁹R¹¹,    —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹,    —R¹⁰OS(O)_(n)R⁹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹, —S(O)_(n)R⁹, —S(O)_(n)Ay,    —S(O)_(n)Het, cyano, azido and nitro;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —R¹⁰cycloalkyl, —OR⁹, —R¹⁰OR⁹,        —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹, —C(O)R⁹, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁹R¹¹,        —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,        —R¹⁰C(NH)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂NR⁹R¹¹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰NHSO₂R⁹, —SO₂R¹⁰, —R¹⁰SO₂R¹⁰, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)w where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   Ay is an aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;    -   n is 0, 1 or 2;-   R² is selected from the group consisting of H, alkyl, cycloalkyl,    alkenyl, cycloalkenyl, —NR⁷R⁸, Ay, —NHR¹⁰Ay, —OR⁷, —OAy,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet,    —NHR¹⁰Het, —OHet and —OR¹⁰Het;-   Y is N;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, cycloalkyl,    alkenyl, Ay, —OR⁷, —OAy, —R¹⁰OR⁷, —R¹⁰OAy, —NR⁷R⁸, —NR⁷Ay,    —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂AY, —SO₂NHR⁹,    Het, —NHHet and —NHR¹⁰Het;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, —R¹⁰cycloalkyl, Ay, —NHR¹⁰Ay, —NR⁷Ay, Het, —NHHet,    —NHR¹⁰Het, —OR⁷, —OAy, —OHet, —R¹⁰OR⁹, —NR⁷R⁸, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,    —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,    —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R₈, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, azido and nitro; or    two adjacent R⁵ groups together with the atoms to which they are    bonded form a C₅₋₆ cycloalkyl or aryl;-   p is 0, 1, 2 or 3;-   each R⁶ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, —R¹⁰cycloalkyl, Ay, Het, —R¹⁰Ay, —R¹⁰Het, —OR⁷, —OAy,    —OHet, —R¹⁰OR⁹, —OR¹⁰Ay, —OR¹⁰Het, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹,    —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸,    —C(O)NR⁷Ay, —C(O)NHR¹⁰Het, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,    —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, azido and nitro; or    two adjacent R⁶ groups together with the atoms to which they are    bonded form a C₅₋₆ cycloalkyl or a 5- or 6-membered heterocyclic    group containing 1 or 2 heteroatoms; and-   M¹ is Li, Mg-halide or cerium-halide, wherein halide is halo.

Generally, the process for preparing compounds of formula (I) wherein Yis N and R² is selected from the group consisting of H, alkyl,cycloalkyl, alkenyl, cycloalkenyl, —NR⁷R⁸, Ay, —NHR¹⁰Ay, —OR⁷, —OAy,—S(O)_(n)R⁹, —S(O)Ay, —R¹⁰NR⁷R⁹, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het,—OHet, and —OR¹⁰Het, (all formulas and all other variables having beendefined above in connection with Scheme 3), comprises the followingsteps:

-   (a) formylating the compound of formula (VII) to prepare a compound    of formula (XI);-   (b) reacting the compound of formula (XII) with a compound of    formula (XVI) to prepare a compound of formula (XVII);-   (c) oxidizing the compound of formula (XVIII) to prepare a compound    of formula-   (d) reacting the compound of formula (XVIII) with a compound of    formula (X) followed by oxidative aromatization to prepare a    compound of formula (XI); and-   (e) when R^(1a) is H or halo, converting the compound of    formula (XI) to a compound of formula (I).

When the compounds of formula (XI) are defined where R^(1a) is H orhalo, the process for preparing compounds of formula (I) comprises theadditional step (e) of converting the compounds of formula (XI) tocompounds of formula (I). Such conversion can be achieved using themethods described below or other suitable methods conventional in theart for this type of transformation.

More specifically, compounds of formula (I) wherein Y is N and R² isselected from the group consisting of H, alkyl, cycloalkyl, alkenyl,cycloalkenyl, —NR⁷R⁸, Ay, —NHR¹⁰Ay, —OR⁷, —OAy, —S(O)_(n)R⁹,—S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet, and—OR¹⁰Het, can be prepared by reacting a compound of formula (XVIII) witha compound of formula (X) followed by oxidative aromatization to preparea compound of formula (XI) and when R^(1a) is H or halo, converting to acompound of formula (I).

-   -   wherein all variables are as defined above in connection with        Scheme 3.

The condensation is conveniently carried out by treating the compound offormula (XVIII) with a compound of formula (X) in an inert solvent,optionally in the presence of a base. The reaction may be heated to50–15° C. or performed at ambient temperature. Suitable inert solventsinclude lower alcohols such as, for example, methanol, ethanol,isopropanol and the like. The base is typically sodium alkoxide,potassium carbonate, or an amine base such as triethylamine. In anotherembodiment, the solvent is N,N-dimethylformamide and the base ispotassium carbonate, or an amine base such as triethylamine. Thereaction produces a dihydropyrimidine intermediate.

Preferably in the same reaction vessel, the dihydropyrimidineintermediate may be oxidized to a compound of formula (XI) by theaddition of an oxidizing agent. The reaction may be heated to 50–150° C.or performed at ambient temperature. Preferrably, the oxidizing agent isoxygen (O₂), palladium on carbon, 2,3-dichloro-5,6dicyano-1,4-benzoquinone, or the like.

Compounds of formula (XVIII) may be conveniently prepared by oxidationof compounds of formula (XVII).

-   -   wherein all variables are as defined above in connection with        Scheme 3.

Preferred oxidizing agents for the oxidation of compounds of formula(XIII) include but are not limited to manganese dioxide, and the like.The oxidation is typically carried out in an inert solvent such as forexample, dichloromethane, chloroform, N,N-dimethylformamide, ether, andthe like.

Compounds of formula (XVII) may be conveniently prepared by reacting acompound of formula (XII) with a compound of formula (XVI).

-   -   wherein M¹ is a metal such as for example, lithium,        magnesium(II) halides, cerium(III) halides, and the like and all        other variables are as defined above in connection with        Scheme 3. Compounds of formula (XVI) may be purchased from        commercial sources or prepared by methods known to one skilled        in the art. The compounds of formula (XII) may be prepared using        the methods described above in connection with Scheme 2.

Compounds of formula (XI) wherein Y is CH or N, and pharmacueticallyacceptable salts, solvates and physiologically functional derivativesthereof, may be conveniently prepared by the process outlined in Scheme4 below.

wherein:

-   X¹ is halo, preferably bromo or iodo;-   R^(1a) is selected from the group consisting of H, halo, alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰Ay,    —R¹⁰Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —R¹⁰R⁹, —R¹⁰NR⁷R⁸,    —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het, —R¹⁰OC(O)R⁹,    —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸,    —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰N HC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,    —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰S(O)_(n)R⁹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, cyano, azido and nitro;    -   each R⁷ and R⁸ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        alkenyl, cycloalkenyl, —R¹⁰cycloalkyl, —OR⁹; —R¹⁰R⁹, —R¹⁰NR⁹R¹¹,        —R¹⁰C(O)R⁹, —C(O)R⁹, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁹R¹¹,        —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,        —R¹⁰C(NH)NR⁹R¹¹, —C(NH)NR⁹R¹¹, —SO₂NR⁹R¹¹, —R¹⁰SO₂NR⁹R¹¹,        —R¹⁰NHSO₂R⁹, —SO₂R¹⁰, —R¹⁰SO₂R¹⁰, —R¹⁰NHCOR⁹ and —R¹⁰SO₂NHCOR⁹;    -   each R⁹ and R¹¹ are the same or different and are independently        selected from the group consisting of H, alkyl, cycloalkyl,        —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)w where w is 1–10, and        —R¹⁰NR¹⁰R¹⁰;    -   each R¹⁰ is the same or different and is independently selected        from the group consisting of alkyl, cycloalkyl, alkenyl,        cycloalkenyl and alkynyl;    -   Ay is an aryl;    -   Het is a 5- or 6-membered heterocyclic or heteroaryl group;    -   n is 0, 1 or 2;-   R² is selected from the group consisting of H, halo, alkyl,    cycloalkyl, alkenyl, cycloalkenyl, —NR⁷R⁸, Ay, —NHR¹⁰Ay, —OR⁷, —OAy,    —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet,    —NHR¹⁰Het, —OHet and —OR¹⁰Het;-   Y is N or CH;-   R³ and R⁴ are the same or different and are each independently    selected from the group consisting of H, halo, alkyl, cycloalkyl,    alkenyl, Ay, —OR⁷, —OAy, —R¹⁰OR⁷, —R¹⁰OAy, —NR⁷R⁸, —NR⁷Ay, —R¹⁰NR    R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹, Het,    —NHHet and —NHR¹⁰Het;-   q is 0, 1, 2, 3, 4 or 5;-   each R⁵ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, —R¹⁰cycloalkyl, Ay, —NHR¹⁰Ay, —NR⁷Ay, Het, —NHHet,    —NHR¹⁰Het, —OR⁷, —OAy, —OHet, —R¹⁰OR⁹, —NR⁷R⁸, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,    —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹,    —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay,    —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,    —R¹¹SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, azido and nitro; or    two adjacent R⁵ groups together with the atoms to which they are    bonded form a C₅₋₆ cycloalkyl or aryl;-   p is 0, 1, 2 or 3;-   each R⁶ is the same or different and is independently selected from    the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, —R¹⁰cycloalkyl, Ay, Het, —R¹⁰Ay, —R¹⁰Het, —OR⁷, —OAy,    —OHet, —R¹⁰OR⁹, —OR¹⁰Ay, —OR¹⁰Het, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹,    —C(O)R⁹, —C(O)Ay, —C(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸,    —C(O)NR⁷Ay, —C(O)NHR¹⁰Het, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,    —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay.    —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,    —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, azido and nitro; or    -   two adjacent R⁶ groups together with the atoms to which they are        bonded form a C₅₋₆ cycloalkyl or a 5- or 6-membered heterocyclic        group containing 1 or 2 heteroatoms; and-   M² is —B(OH)₂, —B(ORa)₂, —B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa,    Mg-halide where Ra is alkyl or cycloalkyl and halide is halo.

Generally, the process for preparing compounds of formula (I) (allformulas and variables having been defined above in connection withScheme 4), comprises the following steps:

-   (a) halogenating a compound of formula (VII) to prepare a compound    of formula (XIX);-   (b) reacting a compound of formula (XIX) with a compound of    formula (XX) to prepare a compound of formula (XI); and-   (c) when R^(1a) is H or halo, converting the compound of    formula (XI) to a compound of formula (I).

When the compounds of formula (XI) are defined where R^(1a) is H orhalo, the process for preparing compounds of formula (I) comprises theadditional step (c) of converting the compounds of formula (XI) to acompound of formula (I). Such conversion can be achieved using themethods described below or other suitable methods conventional in theart for this type of transformation.

More specifically, compounds of formula (XI) can be prepared by reactinga compound of formula (XIX) with a compound of formula (XX).

-   -   wherein all variables are as defined above in connection with        Scheme 4.

The reaction may be carried out in an inert solvent, in the presence ofa palladium (0) or nickel (0) catalyst. The reaction may optionally beheated to about 50–150° C. Preferably the reaction is performed byreacting equimolar amounts of a compound of formula (XIX) with aHet-metal compound of formula (XX), but the reaction may also beperformed in the presence of an excess of compound of the formula (XX).The palladium or nickel catalyst is preferrably present in 1–10 mol %compared to the compound of formula (XIX). Examples of suitablepalladium catalysts include but are not limited to,tetrakis(triphenylphosphine)palladium (0),dichlorobis(triphenyl-phosphine)palladium(II),tris(dibenzylideneacetone)dipalladium (0), andbis(diphenylphosphinoferrocene)palladium (II) dichloride. Suitablesolvents include but are not limited to, N,N-dimethylformamide, toluene,tetrahydrofuran, dioxane, and 1-methyl-2-pyrrolidinone. When theHet-metal compound of formula (XX) is a boronic acid or ester or aborinate the reaction is more conveniently carried out by adding a basein a proportion equivalent to, or greater than, that of the compound offormula (XX). Het-metal compounds of formula (XX) may be obtained fromcommercial sources or prepared either as discreet isolated compounds orgenerated in situ using methods known to one skilled in the art (Suzuki,A. J. Organomet Chem. 1999, 576, 147; Stille, J. Angew. Chem. Int Ed.Engl. 1986, 25, 508; Snieckus, V. J.Org. Chem. 1995, 60, 292.)

Compounds of formula (XIX) can be prepared from compounds of formula(VII) by a halogenation procedure.

-   -   wherein all variables are as defined above in connection with        Scheme 4.

Typically, the halogenation reaction is carried out by subjecting thecompounds of formula (VII) to a halogenating agent in a suitablesolvent. Suitable halogenating agents include but are not limited to,N-bromosuccinimide, trialkylammonium tribromides, bromine,N-chlorosuccinimide, N-iodosuccinimide, iodine monochloride, and thelike. Suitable solvents include, for example, N,N-dimethylformamide,tetrahydrofuran, dioxane, 1-methyl-2-pyrrolidinone, carbontetrachloride, toluene, dichloromethane, diethyl ether, and the like.

The compounds of formula (VII) can be prepared using methods describedabove in connection with Scheme 1.

Alternatively, compounds of formula (XIX) wherein X¹ is bromo may beconveniently prepared from compounds of Formula (XXIII) by abromination/decarboxylation sequence as shown below.

-   -   wherein all variables are as defined above in connection with        Scheme 4.

The compound of formula (XXIII), dissolved in a suitable solvent, istreated with a base followed by a brominating agent and the mixture isstirred at or about 25° C. until the reaction is judged complete by thedisappearance of the compound of formula (XXIII). Suitable solventsinclude, but are not limited to, dimethylformamide, dimethylacetamide,dioxane and the like. The base is preferably sodium hydrogen carbonateand the brominating agent can be, for example, N-bromosuccinimide.

The compounds of formula (XXIII) are prepared according to the methodsdescribed above in connection with Scheme 1.

According to another process of the present invention, compounds offormula (XI) may be conveniently prepared by a process which involvesreacting a ketone of formula (XXI) with an N-aminopyridine derivative offormula (XXII) in the presence of an acid or a base. Typically the acidis p-toluenesulfonic acid and the base can be potassium carbonate,sodium hydroxide, cesium carbonate, lithium hydroxide, triethylamine,potassium tert-butoxide.

wherein X² is I, mesitylsulfonyl and all other variables are as definedabove in connection with Scheme 4.

In the compounds of formula (XI), when R^(1a) is other than H or halo(i.e., R^(1a)═R¹) the forgoing synthesis provide the compounds offormula (I) directly. In the embodiment where compounds of formula (XI)are defined where R^(1a) is H or halo, the compounds of formula (XI) maybe converted to compounds of formula (I). For example, compounds offormula (XI-A) (i.e., compounds of formula (XI) wherein R^(1a) is H) maybe converted to compounds of formula (XI-B) (i.e., compounds of formula(XI) wherein R^(1a) is halo or R¹) by a deprotonation/electrophilequench protocol. For example, the process may be carried out by reactinga compound of formula (XI-A) with a base, such as n-butyllithium,followed by reacting with an electrophilic agent to give compounds offormula (XI-B) wherein E is halo or R¹, or compounds of formula (I).

-   -   wherein E is halo or R¹ and all other variables are as defined        above in connection with any of the processes described above.

Electrophiles which may be used in this process include, but are notlimited to: alkyl halides (E=methyl, benzyl etc.); N-bromosuccinimide(E=bromine); N-chlorosuccinimide (E=chlorine); carbon tetrachloride(E=chlorine); N-iodosuccinimide (E=iodine); aldehydes (E=CH(OH)R¹⁰);dimethylformamide (E=CHO); dimethyl disulfide (E=SMe); carbon dioxide(E=CO₂H); dimethylcarbamoyl chloride (E=C(O)NMe₂) and the like. As willbe apparent, when using the above reagents if the electrophile is ahalide the C-7 substituent is defined as a compound of formula (XI)which is useful as an intermediate en route to a compound of formula(I). The conversion of compounds of formula (XI) wherein R^(1a) is haloto compounds of formula (I) can be achieved using the methods describedbelow or other methods conventional in the art for this type oftransformation.

Each of the foregoing processes may further comprise the step ofconverting the compounds of formula (XI) or (I) to a pharmaceuticallyacceptable salt, solvate, or physiologically functional derivativethereof, using techniques well known to those skilled in the art.

As will be apparent to those skilled in the art, the compounds offormula (I) may be converted to other compounds of formula (I) usingtechniques well known in the art. For example, one method of convertingcompounds of formula (I) to other compounds of formula (I) comprises a)oxidizing the compound of formula (I-A) to prepare a compound of formula(I-B) and then b) optionally reacting a compound of formula (I-B) withan oxygen or amine nucleophile of formula R², wherein R² is selectedfrom the group consisting of —NR⁷R⁸, —NHR¹⁰Ay, —OR⁷, —OAy, Het bondedthrough N, —NHHet, NHR¹⁰Het, OHet and —OR¹⁰Het to produce a compound offormula (I) wherein R² is selected from the group consisting of —NR⁷R⁸,—NHR¹⁰Ay, —OR⁷, —OAy, Het bonded through N, —NHHet, NHR¹⁰Het, OHet and—OR¹⁰Het.

wherein:

-   n′ is 1 or 2;-   R² is selected from the group consisting of H, halo, alkyl,    cycloalkyl, alkenyl, cycloalkenyl, —NR⁷R⁸, —NHR¹⁰Ay, —OR⁷, —OAy, Het    bonded through N, —NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het; and    all other variables are as defined in connection with any of the    processes described above.

More specifically, compounds of formula (I) can be prepared by reactinga compound of formula (I-B) (i.e., compounds of formula I wherein R² isS(O)_(n′)R⁹ where n′ is 1 or 2) with an oxygen or amine nucleophile offormula R², wherein R² is —NR⁷R⁸, —NHR¹⁰Ay, —OR⁷, —OAy, Het bondedthrough N, —NHHet, —NHR¹⁰Het, —OHet and —OR¹⁰Het. The reaction may becarried out neat or in a suitable solvent and may be heated to 50–150°C. Typically the solvent is a lower alcohol such as methanol, ethanol,isopropanol and the like or solvent such as N,N-dimethylformamide ortetrahydrofuran, and the like. Optionally a base may be used tofacilitate the reaction. Typically the base can be potassium carbonate,or an amine base such as triethylamine.

Compounds of formula (I-B) may be conveniently prepared by reacting acompound of formula (I-A) (i.e., compounds of formula I wherein R² is—S(O)_(n)R⁹ where n is 0) with an oxidizing agent in an inert solvent,optionally in the presence of a base. Typically the oxidizing agent is aperacid such as m-chloroperbenzoic acid or the like, optionally with abase such as sodium bicarbonate. Careful monitoring of the stoichiometrybetween the oxidizing agent and the substrate allows the productdistribution between sulfoxide (n=1), and sulfone (n=2) to becontrolled. Suitable solvents include but are not limited to,dichloromethane, chloroform and the like.

Compounds of formula (I-A) are prepared by methods described abovewherein R² is —SR⁹ from the reaction of compounds selected from thegroup consisting of compounds of formula (IX), compounds of formula (XV)and compounds of formula (XVII) with a compound of formula (X-A) (i.e.,the compound of formula (X) wherein R² is —SR⁹). The requisite compoundof formula (X-A) can be obtained from commercial sources or prepared bymethods known to one skilled in the art.

As will be apparent to one skilled in the art, the foregoing conversionmethod is applicable to compounds of formula (XI) (e.g. compounds whereR^(1a) is H or halo) wherein R² is —SR⁹ to form other compounds of theformula (IX) wherein R² is —NR⁷R⁸, —OR⁷, —OAy, Het linked through N,—NHHet, —NHR¹⁰Het, —OHet and —OR¹⁰Het. Such compounds of formula (XI)may be further converted to compounds of formula (I) using methodsdescribed above.

Another particularly useful method for converting compounds of formula(I) to other compounds of formula (I) comprises reacting a compound offormula (I-C) (i.e., a compound of formula (I) wherein R² is fluoro)with an amine such as for example, an amine of formula H—NR⁷R⁸,H—NHR¹⁰Ay, H—NHHet, or H—NHR¹⁰Het, or a heterocyclic or heteroaryl group(Het), and optionally heating the mixture to 50–150° C. to prepare acompound of formula (I-D) (i.e., a compound of formula (I) wherein R² isan amine or substituted amine).

wherein R^(2′) is selected from the group consisting of —NR⁷R⁸,—NHR¹⁰Ay, Het, —NHHet and —NHR¹⁰Het, and all other varaibles are asdefined in connection with any of the processes described above.

This procedure may be carried out by mixing a compound of formula (I-C)in the amine neat, or in a suitable solvent with an excess of amine toproduce a compound of formula (I-D). Typically the solvent is a loweralcohol such as methanol, ethanol, isopropanol and the like. Othersuitable solvents may include N,N-dimethylformamide,1-methyl-2-pyrrolidine and the like.

As will be apparent to one skilled in the art, this method forreplacement of R²=fluoro with an amine in compounds of formula (I) toform other compounds of formula (I) is applicable to analagous sequencesfor compounds of formula (XI) (e.g. compounds where R^(1a) is H orhalo). The newly formed compounds of formula (XI) can be ultimatelyconverted to compounds of formula (I) using methods described herein.

As a further example of conversion of compounds of the formula (XI) tocompounds of the formula (I), the compounds of formula (XI-C), whereinR⁶=6-trifluoromethyl, can be prepared using the techniques describedabove in Schemes 1, 2 and 3 and converted to compounds of the formula(XI-E).

wherein all variables are as defined in connection with any of theprocesses described above.

Compounds of formula (XI-C) can be converted to compounds of formula(XI-D) by treatment with a metal alkoxide in an alcohol solvent.Suitable conditions include the use of sodium ethoxide as the alkoxide,and ethanol as a solvent. The reaction may be heated to 60° C.

A halogenation procedure can be facilitated by treatment of a compoundof formula (XI-D) with a base followed by reaction with a halogenatingagent to provide a compound of formula (XI-E). It will be apparent toone skilled in the art that these compounds of the formula (XI-E) can beconverted to compounds of the formula (I) using any of numerous methodsdescribed herein.

The compounds of formula (XI-C) can be obtained using the proceduresdescribed above in connection with Schemes 1, 2 or 3. In oneparticularly useful embodiment, the compounds of formula (XI-C) areprepared using the procedures described in connection with any ofSchemes 1, 2 or 3, with the exception that the first step, i.e., thepreparation of compounds of formula (IV), involves the condensation of2-chloro-5-trifluoromethylpyridine with the acetophenone of formula(XXX)

under basic conditions, in place of the reaction of the picoline offormula (III) with the benzoylating agent of formula (II).

Compounds of formula (XI-F) may be converted to compounds of formula(I-E) wherein R¹ is selected from the group consisting of alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and —R¹⁰cycloalkyl usingcross coupling methods conventional in the art.

wherein:

-   R¹ is selected from the group consisting of alkyl, alkenyl, alkynyl,    cycloalkyl, cycloalkenyl, and —R¹⁰cycloalkyl;-   M³ is B(OH)₂, B(ORa)₂, B(Ra)₂, Sn(Ra)₃, Zn-halide; Zn—Ra or    Mg-halide, wherein Ra is alkyl or cycloalkyl and halide is halo; and    all other variables are as defined in connection with any of the    processes described above.

The process comprises coupling the compound of formula (XI-F) with atransmetalation partner of the formula R¹-M³. This process can bereadily carried out by mixing a compound of formula (XI-F) with atransmetalation species of formula R¹-M³ in the presence of a catalyticamount of a palladium (0) source. The reactions are typically performedin an inert solvent optionally with heating to 50 to 150° C. Examples ofsuitable palladium catalysts include but are not limited to,tetrakis(triphenylphosphine)palladium (0),dichlorobis(triphenylphosphine)-palladium(II),tris(dibenzylideneacetone)dipalladium (0), andbis(diphenylphosphino-ferrocene)palladium (II) dichloride. Suitablesolvents include but are not limited to, N,N-dimethylformamide, toluene,tetrahydrofuran, dioxane, and 1-methyl-2-pyrrolidinone. Transmetalationspecies of the formula R¹-M³ are available from commercial sources orcan be prepared by methods known to one skilled in the art.

Compounds of formula (XI-F) may be converted to compounds wherein R¹ is—OR⁷ or —OAy as summarized below.

wherein R¹ is —OR⁷ or —OAy and all other variables are as defined inconnection with any of the processes described above.

This transformation is most conveniently carried out by mixing thecompound of formula (XI-F) (preferably where halo is chloro) with anexcess of the alcohol optionally in the presence of an inert solvent,and heating the mixture to about 100–150° C.

As a further example of converting compounds of formula (I) into othercompounds of formula (I), compounds of formula (I-G) (i.e., compounds offormula (I) wherein q is 1 or more and at least one R⁵ is O-methyl) maybe converted to compounds of formula (I-H) (i.e., compounds of formula(I) wherein q is 1 or more and at least one R⁵ is —OH) usingconventional demethylation techniques. Additionally, compounds offormula (I-H) may optionally be converted to compounds of formula (I-J)(i.e., compounds of formula (I) wherein q is 1 or more and at least oneR⁵ is —OR¹⁰). For example, the foregoing conversions are representedschematically as follows:

wherein q′ is 0, 1, 2, 3 or 4, and all other variables are as defined inconnection with any of the processes described above.

The demethylation reaction may be carried out by treating a compound offormula (I-G) in a suitable solvent with a Lewis acid at a temperatureof −78° C. to room temperature, to produce a compound of formula (I-H).Typically the solvent is an inert solvent such as dichloromethane,chloroform, acetonitrile, toluene and the like. The Lewis acid may beboron tribromide, trimethylsilyl iodide and the like.

Optionally, the compounds of formula (I-H) may be further converted tocompounds of formula (I-J) by an alkylation reaction. The alkylationreaction may be carried out by treating a compound of formula (I-H) insuitable solvent with an alkyl halide of formula R¹⁰-Halo where R¹⁰ isas defined above, to form a compound of formula (I-J). The reaction ispreferably carried out in the presence of a base and with optionallyheating to 50–200° C. The reaction may be carried out in solvents suchas N,N-dimethylformamide, dimethylsulfoxide and the like. Typically thebase is potassium carbonate, cesium carbonate, sodium hydride or thelike. Additionally, as will be apparent to those skilled in the art, thealkylation reaction can be carried out under Mitsunobu conditions.

In yet another example, compounds of formula (I-K) (i.e., compounds offormula (I) wherein q is 1 or more and at least one R⁵ is halo) orcompound of formula (I-M) (i.e. compounds of formula (I) wherein q is 1or more and at least one R⁵ is nitro) can be converted to compounds offormula (I-L) (i.e., compounds of formula (I) wherein q is 1 or more andat least one R⁵ is NH₂). Optionally, compounds of formula (I-L) may thenbe converted to compounds of formula (I-N) (i.e., compounds of formula(I) wherein q is 1 or more and at least one R⁵ is —NR⁷R⁸ where R⁷ and R⁸are not both H). For example, the foregoing conversions are representedschematically as follows:

wherein q′ is 1, 2, 3 or 4 and all other variables are as defined inconnection with any of the processes described above.

The process of converting compounds of formula (I-K) to compounds offormula (I-L) is carried out by reacting a compound of formula (I-K)with an imine in the presence of a palladium (0) source, a base and asuitable ligand, followed by hydrolysis to give a compound of formula(I-L). See J. Wolfe, et al., Tetrahedron Letters 38:6367–6370 (1997).Typically the imine is benzophenoneimine, the palladium (0) source istris(dibenzylideneacetone)dipalladium(0), the base is sodiumtert-butoxide and the ligand isracemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. Suitable solventsinclude N,N-dimethylformamide and the like.

Compounds of formula (I-L) can also be obtained from compounds offormula (I-M) by reduction. The reduction can conveniently be carriedout by using zinc, tin or iron and acid, by using tin(II)chloride, or byusing palladium or platinium catalysts under hydrogen atmosphere in asuitable solvent as obvious to one skilled in the art of organicsynthesis.

Reaction of a compound of formula (I-L) with compound of formulaR⁷-halogen in a suitable solvent in the presence of base, optionallywith heating may be used to prepare compounds of formula (I-N).Typically the base is triethylamine or pyridine and the solvent isN,N-dimethylformamide and the like.

Additional compounds of formula (I-N) can be obtained by reductiveamination of compounds of formula (I-L) with ketones or aldehydes. See,A. Abdel-Magid, et al., J. Org. Chem. 61:3849–3862 (1996). Typically acompound of formula (I-L) is treated with an aldehyde or a ketone in thepresence of an acid, such as acetic acid, and a reducing agent, such assodium triacetoxyborohydride and the like, in an inert solvent such asdichloroethane and the like.

Other transformations well known to those skilled in the art for usewith anilines may be used to convert compounds of formula (I-L) tocompounds of formula (I-N).

Based upon this disclosure and the examples contained herein one skilledin the art can readily convert compounds of formula (I) or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof into other compounds of formula (I), or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof.

The present invention also provides radiolabeled compounds of formula(I) and biotinylated compounds of formula (I). Radiolabeled compounds offormula (I) and biotinylated compounds of formula (I) can be preparedusing conventional techniques. For example, radiolabeled compounds offormula (I) can be prepared by reacting the compound of formula (I) withtritium gas in the presence of an appropriate catalyst to produceradiolabeled compounds of formula (I).

In one preferred embodiment, the compounds of formula (I) are tritiated.

The radiolabeled compounds of formula (I) and the biotinylated compoundsof formula (I) are useful in assays for the identification of compoundsfor the treatment or prophylaxis of viral infections such as herpesviral infections. Accordingly, the present invention provides an assaymethod for identifying compounds which have activity for the treatmentor prophylaxis of viral infections such as herpes viral infections,which method comprises the step of specifically binding the radiolabeledcompound of formula (I) or the biotinylated compound of formula (I) tothe target protein. More specifically, suitable assay methods willinclude competition binding assays. The radiolabeled compounds offormula (I) and the biotinylated compounds of formula (I) can beemployed in assays according to the methods conventional in the art.

The following examples are illustrative embodiments of the invention,not limiting the scope of the invention in any way. Reagents arecommercially available or are prepared according to procedures in theliterature. Example numbers refer to those compounds listed in thetables above. ¹H and ¹³C NMR spectra were obtained on Varian Unity PlusNMR spectrophotometers at 300 or 400 MHz, and 75 or 100 MHzrespectively. ¹⁹F NMR were recorded at 282 MHz. Mass spectra wereobtained on Micromass Platform, or ZMD mass spectrometers from MicromassLtd. Altrincham, UK, using either Atmospheric Chemical Ionization (APCI)or Electrospray Ionization (ESI). Analytical thin layer chromatographywas used to verify the purity of some intermediates which could not beisolated or which were too unstable for full characterization, and tofollow the progress of reactions. Unless otherwise stated, this was doneusing silica gel (Merck Silica Gel 60 F254). Unless otherwise stated,column chromatography for the purification of some compounds, used MerckSilica gel 60 (230–400 mesh), and the stated solvent system underpressure. All compounds were characterized as their free-base formunless otherwise stated. On occasion the corresponding hydrochloridesalts were formed to generate solids where noted.

EXAMPLE 1 2-(4-Fluorophenyl)-3-(4-pyrimidinyl)-pyrazolo[1,5-a]pyridine

a) 1-(4-Fluorophenyl)-2-(4-pyrimidinyl)-ethanone.

To a stirred solution of 4-methylpyrimidine (20.64 g, 0.22 mol) andethyl 4-fluorobenzoate (36.9 g, 0.22 mol) in dry tetrahydrofuran (100mL) at 0° C. under nitrogen was added lithium bis(trimethylsilyl)amide(1M in tetrahydrofuran, 440 mL, 0.44 mol) over a 2 hour period. A whiteprecipitate deposited during the addition and this suspension wasstirred at room temperature overnight The reaction was diluted with 100mL of water and filtered. The filtrate was washed with water three timesand dried. The solution was diluted with ethyl acetate (100 mL) and theorganic phase separated. The aqueous phase was further extracted withethyl acetate (100 mL). Organic phases were dried over magnesium sulfateand concentrated and combined with the filtrate to give a combined yieldof 47 g (98%) of product. ¹H NMR (CDCl₃) exists as a 2:1 mixture ofenol:keto tautomers: δ enol form: 5.95 (s, 1H), 6.92 (dd, J=1.2, 5.7 Hz,1H), 7.06–7.14 (m, 2H), 7.83 (dd, J=5.4, 8.7 Hz, 2H), 8.40 (d, J=5.7 Hz,1H), 8.8 (s, 1H); keto form: 4.42 (s, 2H), 7.12–7.18 (m, 2H), 7.34 (d,J=4.2 Hz, 1H), 8.06 (dd, J=5.3, 8.8 Hz, 2H), 8.67 (d, J=5.1 Hz, 1H),9.16 (s, 1H); APESI−MS m/z 215 (M−1)⁻.

b) A solution of 1-(4-fluorophenyl)-2-(4-pyrimidinyl)-ethanone (21.6 g,0.1 mol), 1-aminopyridinium iodide (22.2 g, 0.1 mol) and potassiumcarbonate (41.4 g, 0.3 mol) in a mixture of water (300 mL) andisopropanol (300 mL) was heated and stirred at 100° C. for 16 hours. Theisopropanol was removed under vacuum and the resulting aqueous phaseextracted with dichloromethane (5×200 mL). The dichloromethane extractswere combined and the solvent evaporated under reduced pressure to leavea red solid which was purified by silica gel chromatography eluting witha hexanelethyl acetate to give the title compound as a yellow solid,9.16 g (32%). ¹H NMR (DMSO-d₆): δ 7.07 (d, J=5.4 Hz, 1H), 7.14 (t, J=6.8Hz, 1H), 7.32 (t, J=8.7 Hz, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.60 (dd,J=5.7, 8.7 Hz, 2H), 8.40 (d, J=8.9 Hz, 1H), 8.54 (d, J=5.3 Hz, 1H), 8.83(d, J=7.1 Hz, 1H), 9.16 (s, 1H), APESI+MS m/z 291 (M+1).

EXAMPLE 22-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-pyrazolo[1,5-a]pyridine

a) 1-(4-Fluorophenyl)-2-(4-(2-methylthio)pyrimidinyl)ethanone.

To a stirred solution of 2-methylthio-4-methylpyrimidine (66 g, 0.47mol) and ethyl 4-fluorobenzoate (79 g, 0.47 mol) in dry tetrahydrofuran(400 mL) at 0° C. under nitrogen was added lithiumbis(trimethylsilyl)amide (1N in tetrahydrofuran, 940 mL, 0.94 mol) overa 2 hour period. The solution was stirred at ice bath temperature for 18hours. The solution was poured into 2 L of ice cold 0.5 N hydrochloricacid. A precipitate formed which was filtered off and air dried. Secondand third crops of solids were obtained as the precipitate was washedwith water. The combined precipitates were recrystalized from acetoneand water to give product as a yellow solid: 117 g (95%). ¹H NMR(CDCl₃): δ (all in enol form): 3.0 (s, 3H), 6.29 (s, 1H), 7.01 (d, J=5.7Hz, 1H), 7.48 (t, J=8.7 Hz, 2H), 8.20 (dd, J=5.4, 8.8 Hz, 2H), 8.68 (d,J=5.7 Hz, 1H); APESI−MS m/z 261 (M−1)⁻.

b) A solution of1-(4-fluorophenyl)-2-(4-(2-methylthio)pyrimidinyl)ethanone (13.0 g, 50mmol) in isopropanol (300 mL) was warmed to reflux. A solution of1-aminopyridinium iodide (14 g, 63 mmol) in water (300 mL) was treatedwith 2N sodium hydroxide (31.5 mL). This solution was added to theketone over a period of two hours while the mixture was heated atreflux. After an additional seven hours, the isopropanol was partiallyevaporated under reduced pressure and the resulting solution wasextracted with dichloromethane (2×300 mL). The dichloromethane extractswere combined, dried (magnesium sulfate), filtered and the solventevaporated under reduced pressure to leave a red solid which waspurified by silica gel chromatography with dichloromethane to give thetitle compound as a yellow solid, 4.5 g (26%). ¹H NMR (DMSO-d₆): δ 2.5(s, 3H), 6.80 (d, J=5.3 Hz, 1H), 7.18 (t, J=6.9 Hz, 1H), 7.36 (t, J=8.8Hz, 2H), 7.59 (t, J=7.9 Hz, 1H), 7.60 (dd, J=5.7, 8.7 Hz, 2H), 8.38 (d,J=9.1 Hz, 1H), 8.40 (d, J=5.3 Hz, 1H), 8.88 (d, J=7.0 Hz, 1H), APESI+MSm/z 337 (M+1).

EXAMPLE 32-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-pyrazolo[1,5-a]pyridine

To a stirred solution of2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-pyrazolo[1,5-a]pyridine(0.285 g, 0.85 mmol) in dichloromethane (10 mL) was added, dropwise, asolution of (0.257 g, 0.85–1.23 mmol) of 57–86% m-chloroperoxybenzoicacid in dichloromethane (5 mL). After 10 minutes, the solution wasquenched by the addition of aqueous potassium carbonate (20 mL), and theorganic phase was separated. The aqueous phase was further extractedwith dichloromethane (2×20 mL) and the dichloromethane phases dried overmagnesium sulfate filtered and concentrated to give a crude white solid.Chromatography on silica gel eluting with a hexane/Ethyl acetategradient (0–100% ethyl acetate) gave the title compound as a whitesolid, 0.213 g (60: ¹H NMR (CDCl₃): δ 3.05 (s, 3H), 7.07–7.11 (m, 2H),7.25 (d, J=8.5 Hz, 2H), 7.55 (t, J=7.8 Hz, 1H), 7.64 (dd, J=5.5, 6.9 Hz,2H), 8.52 (d, J=5.1 Hz, 1H), 8.59 (d, J=6.9 Hz, 1H), 8.84 (d, J=9.0 Hz,1H); APESI+MS m/z 353 (M+1)⁻.

EXAMPLE 4N-Butyl-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

A solution of2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-pyrazolo[1,5-a]pyridine(Example 3, 0.03 g 0.085 mmol) in n-butylamine (0.5 mL) was heated toreflux for 0.25 hours. On cooling a white solid deposits, which wascollected by filtration, washed with hexane and dried under vacuum togive the title compound as a white solid, 0.029 g (94%). ¹H NMR(DMSO-d₆): δ 0.87 (t, J=7.4 Hz, 3H), 1.31 (sextet, J=7.4 Hz, 2H),1.49(quintet, J=7.2 Hz, 2H), 3.25 (q, J=6.6 Hz, 2H), 6.4 (bs, 1H), 7.06(t, J=6.8 Hz, 1H), 7.13 (bs, 1H), 7.29 (t, J=8.8 Hz, 2H), 7.43 (t, J=7.8Hz, 1H), 7.59 (dd, J=5.7, 8.5 Hz, 2H), 8.01 (d, J=5.3 Hz, 1H), 8.40 (bs,1H), 8.76 (d, J=6.9 Hz, 1H); APESI+MS m/z 362 (M+1)⁻.

EXAMPLE 52-(4-Fluorophenyl)-7-methyl-3-(4-pyrimidinyl)pyrazolo[1,5-a]pyridine

A solution of2-(4-fluorophenyl)-3-(4-pyrimidinyl)-pyrazolo[1,5-a]pyridine (Example 1,0.2 g, 0.69 mmol) in dry tetrahydrofuran (5 mL) was cooled to −78° C.under nitrogen and lithium diisopropylamide (0.45 mL of a 2M solution inheptane/tetrahydrofuran/ethylbenzene, 0.9 mmol) was added dropwise. Thereaction mixture was stirred for about 10 minutes and methyl iodide (0.2mL, 4 mmol) was added. The solution was allowed to warm to roomtemperature and stirred for a further 1.5 hours. The reaction mixturewas diluted with diethyl ether (20 mL), water (20 mL) added, and theorganic phase separated. The aqueous phase was further extracted withether (20 mL) and the combined ether phases were dried over anhydrousmagnesium sulfate, filtered and the solvents evaporated to give a yellowsolid. Chromatography on silica gel eluting with 9:1 hexane/ethylacetate gave the title compound, 0.080 g (38%). ¹H NMR (DMSO-d₆): δ 2.72(s, 3H), 7.05 (d, J=6.3 Hz, 2H), 7.32 (t, J=8.8 Hz, 2H), 7.46 (dd,J=7.0, 8.6 Hz, 1H), 7.61 (dd, J=5.5, 8.6 Hz, 2H), 8.32 (d, J=9.0 Hz,1H), 8.52 (d, J=5.5 Hz, 1H), 9.15 (s, 1H); APESI+MS m/z 305 (M+1)⁻.

EXAMPLE 62-(4-Fluorophenyl)-7-methylthio-3-(4-pyrimidinyl)pyrazolo[1,5-a]pyridine

In a similar manner as described in Example 5, using dimethyl disulfidein place of methyl iodide, was obtained the title compound, (72%). ¹HNMR (DMSO-d₆): δ 2.46 (s, 3H), 7.01 (d, J=7.3 Hz, 1H), 7.06 (d, J=4.7Hz, 1H), 7.33 (t, J=8.8 Hz, 2H), 7.53 (t, J=8.2 Hz, 1H), 7.61 (dd,J=5.5, 8.4 Hz, 2H), 8.22 (d, J=8.8 Hz, 1H), 8.53 (d, J=5.5 Hz, 1H), 9.15(s, 1H); APCI+MS m/z 336 (M)⁻.

EXAMPLE 72-(4-Fluorophenyl)-7-methylsulfinyl-3-(4-pyrimidinyl)pyrazolo[1,5-a]-pyridine

To a stirred solution of2-(4-fluorophenyl)-7-methylthio-3-(4-pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 6, 0.246 g, 0.73 mmol) in chloroform (20 mL) was added,dropwise, a solution of of m-chloroperbenzoic acid (57–86%, 0.221 g,0.73–1.1 mmol) in chloroform (10 mL). After 1 hour, the reaction wasquenched by the addition of aqueous potassium carbonate (20 mL), and theorganic phase was separated. The aqueous phase was further extractedwith chloroform (2×20 mL) and the combined chloroform phases were driedover anhydrous magnesium sulfate. The drying agent was removed byfiltration and the solvent was evaporated to give a light brown solid.Chromatography on silica gel eluting with a hexane/ethyl acetategradient (0–30% ethyl acetate) gave the title compound as the majorproduct, 0.170 g (66%). ¹H NMR (DMSO-d₆): δ 3.11 (s, 3H), 7.13 (d, J=5.4Hz, 1H), 7.33 (t, J=8.8 Hz, 2H), 7.50 (d, J=7.0 Hz, 1H), 7.63 (dd,J=5.7, 8.6 Hz, 2H), 7.76 (dd, J=7.4, 8.1 Hz, 1H), 8.50 (d, J=8.8 Hz,1H), 8.60 (d, J=5.5 Hz, 1H), 9.20 (s, 1H); APESI+MS m/z 353 (M+1)⁻.

EXAMPLE 87-(2-Fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-pyrazolo[1,5-a]pyridine

a)7-(2-Fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-pyrazolo[1,5-a]pyridine.

To a stirred solution of 2-fluoroethanol (0.128 g, 2 mmol) intetrahydrofuran (5 mL), under nitrogen, was added potassiumtert-butoxide (1M in tert-BuOH. 2.0 mL, 2 mmol) and the resultingsolution stirred for 5 minutes. A solution of7-chloro-2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)pyrazolo[1,5-a]pyridine(0.15 g, 0.4 mmol) in dichloromethane (0.5 mL) was then added dropwiseand the reaction stirred for 16 hours. Dichloromethane (20 mL) and water(20 mL) were added and the aqueous phase was separated. The aqueousphase was further extracted with dichloromethane (2×20 mL) and thecombined organic phases were dried over anhydrous magnesium sulfate andthe solvents evaporated to give a brown solid. Purification on silicagel using 4:1 hexane/ethyl acetate as eluent gave the title compound,0.111 g (70%). ¹H NMR (CDCl₃): δ 2.59 (s, 3H), 4.60 (t, J=4.1 Hz, 1H),4.67 (t, J=4.1 Hz, 1H), 4.87 (t, J=4.1 Hz, 1H), 4.98 (t, J=4.1 Hz, 1H),6.37 (d, J=7.3 Hz, 1H), 6.64 (d, J=5.3 Hz, 1H), 7.13 (t, J=8.6 Hz, 2H),7.37 (t, J=8.2 Hz, 1H), 7.58 (dd, J=5.3, 8.6 Hz, 2H), 8.15 (d, J=8.8 Hz,1H), 8.21 (d, J=5.5 Hz, 1H); APESI+MS m/z 399 (M+1)⁻.

b)7-Chloro-2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)pyrazolo[1,5-a]pyridine.

A solution of2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-pyrazolo[1,5-a]pyridine(Example 2, 1.0 g, 3.0 mmol) in tetrahydrofuran (20 mL) was cooled tounder nitrogen, lithium diisopropylamide (2M solution inheptane/tetrahydrofuran/ethylbenzene, 3.0 mL, 6.0 mmol) was addeddropwise. The solution was stirred for 5 minutes then a solution oftoluenesulfonyl chloride (1.2 g, 6.3 mmol) in tetrahydrofuran (5 mL) wasadded dropwise and the reaction mixture was stirred for 1 hour at −78°C. and then allowed to warm to room temperature. Ethyl acetate (30 mL)and water (20 mL) were added and the organic phase was separated. Theaqueous phase was extracted with Ethyl acetate (3×20 mL) and thecombined ethyl acetate phases were dried over magnesium sulfate filteredand the solvent was evaporated to give a brown oil. Purification onsilica gel using 1:1 hexane/dichloromethane as eluent gave7-chloro-2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)pyrazolo[1,5-a]pyridine,0.316 g (28%). ¹H NMR (CDCl₃): δ 2.65 (s, 3H), 6.73 (d, J=5.4 Hz, 1H),7.12–7.25 (m, 3H), 7.39 (dd, J=7.4, 8.9 Hz, 1H), 7.62–7.69 (m, 2H), 8.30(d, J=5.2 Hz, 1H), 8.50 (d, J=8.1 Hz, 1H); APEI+MS m/z 371/373 (M+1)⁻.

EXAMPLE 9N-Butyl-4-[7-(2-fluoroethoxy)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

In a similar manner as described in Example 4, from7-(2-fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 24) and n-butylamine was obtained the title compound, (68%). ¹HNMR (CDCl₃): δ 0.96 (t, J=7.3 Hz, 3H), 1.44 (sextet, J=7.5 Hz, 2H), 1.62(quintet, J=7.5 Hz, 2H), 3.45 (q, J=6.5 Hz, 2H), 4.59 (t, J=4.1 Hz, 1H),4.66 (t, J=4.1 Hz, 1H), 4.86 (t, J=4.1 Hz, 1H), 4.98 (t, J=4.1 Hz, 1H),5.4 (bs, 1H), 6.26 (d, J=5.3 Hz, 1H), 6.32 (d, J=7.3 Hz, 1H), 7.11 (t,J=8.7 Hz, 2H), 7.30 (t, J=7.8 Hz, 1H), 7.60 (dd, J=5.4, 8.6 Hz, 2H),8.01 (d, J=5.1 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H); APESI+MS m/z 424 (M+1)⁻.

EXAMPLE 10N-Benzyl-4-[7-(2-fluoroethoxy)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

In a similar manner as described in Example 4, from7-(2-fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 24) and benzylamine was obtained the title compound, (73%). ¹HNMR (CDCl₃): δ 4.56 (t, J=4.1 Hz, 1H), 4.64 (t, J=4.1 Hz, 1H), 4.72 (d,J=5.7 Hz, 2H), 4.85 (t, J=4.1 Hz, 1H), 4.96 (t, J=4.1 Hz, 1H), 5.7 (bs,1H), 6.28–6.31 (m, 2H), 7.08–7.16 (m, 3H), 7.26–7.30 (m, 1H), 7.34 (d,J=7.9 Hz, 2H), 7.39 (t, J=6.5 Hz, 2H), 7.60 (dd, J=5.5, 8.6 Hz, 2H),7.75 (bs, 1H), 8.01 (d, J=5.1 Hz, 1H); APESI+MS m/z 458 (M+1)⁻.

EXAMPLE 112-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-7-(2,2,2-trifluoro-ethoxy)pyrazolo[1,5-a]pyridine

a)2-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-7-(2,2,2-trifluoro-ethoxy)pyrazolo[1,5-a]pyridine.

A solution of7-chloro-2-(4-fluorophenyl)-3-(4-(2-methylthio)-pyrimidinyl)pyrazolo[1,5-a]pyridine(1.6 g, 4.3 mmol) in dichloromethane (100 mL), was cooled in an icebath. To this solution was added a solution of 2,2,2-trifluoroethanol(1.6 mL, 22 mmol) and potassium tert-butoxide (22 mL of a 1M solution intert-butanol) in tetrahydrofuran (50 mL). The reaction mixture wassubsequently warmed to 60° C. for 18 h, then poured into cold water andneutralized with 1 N HCl. The phases were separated, and the organicswere washed with water (2×50 mL), dried (magnesium sulfate), filtered,and evaporated under reduced pressure. The residue was purified bysilica gel chromatography with ethyl acetate:hexane (1:2) to give thetitle compound as a yellow solid, 1.6 g (86%): ¹H NMR (CDCl₃): δ 2.65(s, 3H), 4.86 (q, J=8.0 Hz, 2H), 6.56 (d, J=7.4 Hz, 1H), 6.73 (d, J=5.4Hz, 1H), 7.20 (t, J=8.6 Hz, 2H), 7.42 (t, J=8.3 Hz, 1H), 7.65 (dd, J=5.5Hz, 8.8 Hz, 2H), 8.28 (d, J=8.9 Hz, 1H), 8.29 (d, J=5.2 Hz, 1H);APESI+MS m/z 435 (M+1).

b)7-Chloro-2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)pyrazolo[1,5-a]-pyridine.

2-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)pyrazolo[1,5-a]pyridine(17 g, 50 mmol) (see Example 2) was dissolved in tetrahydrofuran andcooled to −78° C. in a dry ice/acetone bath. Lithium diisopropylamide(2M solution in tetrahydrofuran, 76 mL, 0.152 mol) was added. After 20min, carbon tetrachloride (88 mL, 910 mmol) was added. After 2 h, thesolution was quenched with saturated brine (50 mL), and layersseparated. The organics were washed with saturated brine (100 mL), dried(magnesium sulfate), filtered and concentrated. The residue was purifiedby silica gel chromatography with dichloromethane to give the titlecompound as a yellow solid, 15 g (80%). ¹H NMR (CDCl₃): δ 2.67 (s, 3H),4.86 (q, J=8.0 Hz, 2H), 6.57 (d, J=7.4 Hz, 1H), 6.75 (d, J=5.4 Hz, 1H),7.21 (t, J=8.6 Hz, 2H), 7.45 (t, J=8.2 Hz, 1H), 7.65 (dd, J=5.4 Hz, 8.7Hz, 2H), 8.28 (apparent d, J=8.1 Hz, 2H); APESI+MS m/z 371 (M+1).

EXAMPLE 12N-Butyl-4-[2-(4fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

In a similar manner as descibed in Example 4, from2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine(Example 25) and n-butylamine was obtained the title compound as a whitesolid, (31%). ¹H NMR (CDCl₃): δ 1.02 (t, J=7.3 Hz, 3H), 1.51 (sextet,J=7.5 Hz, 2H), 1.72 (quintet, J=7.5 Hz, 2H), 3.51 (q, J=7.0 Hz, 2H),4.86 (q, J=8.1 Hz, 2H), 5.2 (bs, 1H), 6.35 (d, J=5.3 Hz, 1H), 6.52 (d,J=7.2 Hz, 1H), 7.17 (t, J=8.7 Hz, 2H), 7.35 (dd, J=7.6, 8.8 Hz, 2H),7.68 (dd, J=5.4, 8.6 Hz, 2H), 8.10 (d, J=5.3 Hz, 1H), 8.21 (d, J=8.9 Hz,1H); APESI+MS m/z 460 (M+1)⁻.

EXAMPLE 13N-Benzyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]-pyridin-3-yl]-2-pyrimidinamine

In a similar manner as described in Example 4, from2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine(Example 25, 0.034 g, 0.076 mmol) and benzylamine was obtained the titlecompound, 0.03 g (80%). ¹H NMR (CDCl₃): δ 4.65 (d, J=5.8 Hz, 2H), 4.72(dd, J=8.1, 16.3 Hz, 2H), 5.6 (bs, 1H), 6.27 (d, J=5.3 Hz, 1H), 6.36 (d,J=7.3 Hz, 1H), 7.07 (t, J=8.6 Hz, 3H), 7.23–7.29 (m, 1H), 7.29–7.35 (m,4H), 7.56 (dd, J=5.7, 8.5 Hz, 2H), 7.7 (bs, 1H), 8.00 (d, J=5.3 Hz, 1H);APESI+MS m/z 494 (M+1)⁻.

EXAMPLE 14N-Cyclopropyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

2-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)-pyrazolo[1,5-a]pyridine(Example 25, 1.4 g 3.1 mmol) was dissolved in dichloromethane (50 mL)and treated with cyclopropylamine (10 mL, 61 mmol). The solution washeated at reflux for six days, cooled to room temperature and thendiluted with dichloromethane. The solution was washed with saturatedsodium bicarbonate (25 mL) and water (25 mL), dried (magnesium sulfate),filtered and the solvent evaporated under reduced pressure. The residuewas purified by silica gel chromatography with ethyl acetate:hexane(1:1) as eluent to give the title compound as a white solid, 1.1 g(80%): ¹H NMR (acetone-d₆): δ 0.47 (br. s, 2H), 0.66 (br. s, 2H), 2.70(m, 1H), 5.02 (q, J=8.2 Hz, 2H), 6.22 (d, J=5.2 Hz, 1H), 6.41 (br. s,1H), 6.62 (d, J=7.2 Hz, 1H), 7.15 (t, J=8.5 Hz, 2H), 7.33 (t, J=8.1 Hz,1H), 7.60 (m, 2H), 7.94 (d, J=5.1 Hz, 1H), 8.34 (br. s, 1H); APESI+MSm/z 444 (M+1).

EXAMPLE 15N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

2-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)-pyrazolo[1,5-a]pyridine(Example 25, 0.05 g, 0.11 mmol) was dissolved in cyclopentylamine (1 mL)and heated at 60° C. for 18 hours. The reaction mixture was diluted withethyl acetate (40 mL) and extracted with water (2×10 mL). The organiclayer was dried (magnesium sulfate), filtered and the solvent wasevaporated under reduced pressure. The residue was purified on a silicagel preparative chromatography plate (2 mm) with ethyl acetate:hexanes(1:2) as eluent to give the title compound, 0.008 g (15%). ¹H NMR(acetone-d₆): δ 1.60 (m, 4H), 1.75 (m, 2H), 2.04 (m, 2H), 4.32 (m, 1H),5.13 (q, J=8.4 Hz, 2H), 6.23 (br. s, 1H), 6.30 (d, J=4.7 Hz, 1H), 6.73(d, J=7.5 Hz, 1H), 7.25 (t, J=8.7 Hz, 2H), 7.43 (t, J=8.1 Hz, 1H), 7.70(dd, J=5.5 Hz, 8.8Hz, 2H), 8.04 (d, J=5.1 Hz, 1H), 8.24 (d, J=9 Hz, 1H);APESI+MS m/z 472 (M+1).

EXAMPLE 16N-Cyclohexyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

In a similar manner as described in Example 15 from2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 25) was obtained the title compound, (49%). ¹H NMR(acetone-d₆): δ1.3 (m, 5H), 1.60 (m, 1H), 1.80 (m, 2H), 2.00 (m, 2H),3.80 (m, 1H), 5.13 (q, J=8.4 Hz, 2H), 6.12 (br s, 1H), 6.30 (br s, 1H),6.73 (d, J=7.5 Hz, 1H), 7.25 (t, J=8.7 Hz, 2H), 7.43 (t, J=8.1 Hz, 1H),7.69 (dd, J=5.5 Hz, 8.6 Hz, 2H), 8.04 (d, J=5.1 Hz, 1H), 8.22 (d, J=8.9Hz, 1H); APESI+MS m/z 485 (M+1).

EXAMPLE 173-(4-[2-(4-Fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinylamino)-1-propanol

In a similar manner as described in Example 15. From2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 25) was obtained the title compound, (38%). ¹H NMR(acetone-d₆): δ 1.69 (m, 2H), 3.44 (apparent q, J=6.4 Hz, 2H), 3.53 (brs, 2H), 3.75 (br. s, 1H), 5.01 (q, J=8.4 Hz, 2H), 6.19 (d, J=5.2 Hz,1H), 6.32 (br.s, 1H), 6.62 (d, J=7.5 Hz, 1H), 7.14 (t, J=8.9 Hz, 2H),7.32 (t, J=8.2 Hz, 1H), 7.59 (dd, J=5.6 Hz, 8.6 Hz, 2H), 7.93 (d, J=5.2Hz, 1H), 8.14 (d, J=8.9 Hz, 1H); APESI+MS m/z 462 (M+1).

EXAMPLE 182-(4-Fluorophenyl)-3-(4-(2-methyloxy)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine

2-(4-Fluorophenyl)-7-(2,2,2-trifluoroethoxy)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine (Example 25) (0.05 g, 0.11 mmol) was dissolvedin 2 N ammonia in methanol (20 mL) and the mixture was heated at 80° C.for 18 hours. The reaction mixture was diluted with ethyl acetate (40mL) and extracted with water (2×10 mL). The organic layer was dried(magnesium sulfate), filtered and evaporated under reduced pressure. Theresidue was purified on a silica gel preparative chromatography plate (2mm) with ethyl acetate:hexane (1:2) as eluent to give the titlecompound, 0.034 g (73%). ¹H NMR (CDCl₃) δ 4.12 (s, 3H), 4.86 (q, J=8.0Hz, 2H), 6.56 (d, J=7.4 Hz, 1H), 6.71 (d, J=5.2 Hz, 1H), 7.21 (t, J=8.5Hz, 2H), 7.42 (t, J=8.2 Hz, 1H), 7.65 (dd, J=5.4 Hz, 7.7 Hz, 2H), 8.30(d, J=5.2 Hz, 1H), 8.35 (d, J=8.9 Hz, 1H); APESI+MS m/z 419 (M+1).

EXAMPLE 192-(4-Fluorophenyl)-3-(4-(2-phenyloxy)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine

2-(4-Fluorophenyl)-7-(2,2,2-trifluoroethoxy)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 25) (0.05 g, 0.11 mmol) was dissolved in dichloromethane (3 mL)and treated with a solution of phenol (0.1 mL, 1.1 mmol) and potassiumtert-butoxide (1.2 mL of a 1 N in tert-butyl alcohol) in tetrahydrofuran(3 mL). After 30 min at ambient temperature, the reaction was quenchedwith water and diluted with ethyl acetate (40 mL) and extracted withwater (2×10 mL). The organic layer was dried (magnesium sulfate),filtered and evaporated under reduced pressure. The residue was purifiedon a silica gel preparative chromatography plate (2 mm) with ethylacetate:hexane (1:2) as eluent to give the title compound, 0.032 g(61%). ¹H NMR (CDCl₃): δ 4.81 (q, J=8.0 Hz, 2H), 6.49 (d, J=7.4 Hz, 1H),6.74 (d, J=5.4 Hz, 1H), 7.17 (t, J=7.7 Hz, 1H), 7.23 (t, J=8.6 Hz, 2H),7.32 (d, J=7.7 Hz, 2H), 7.36 (t, J=7.4 Hz, 1H), 7.53 (t, J=7.7 Hz, 2H),7.63 (dd, J=5.4 Hz, 8.6 Hz, 2H), 7.76 (d, J=8.8 Hz, 1H), 8.31 (d, J=5.4Hz, 1H); APESI+MS m/z 481 (M+1).

EXAMPLE 202-(4-Fluorophenyl)-3-(4-(2-(2,2,2-trifluoroethoxy))pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine

In a similar manner as described in Example 8, from2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(ethylsulfinyl)pyrazolo[1,5-a]pyridine(Example 21) and 2,2,2-trifluoroethanol was obtained the title compound,(10%). ¹H NMR (CDCl₃): δ 4.78–4.85 (m, 4H), 6.52 (d, J=7.3 Hz, 1H), 6.75(d, J=5.3 Hz, 1H), 7.16 (t, J=8.6 Hz, 2H), 7.41 (t, J=8.2 Hz, 1H), 7.58(dd, J=5.3, 8.6 Hz, 2H), 8.22 (d, J=8.8 Hz, 1H), 8.25 (d, J=5.3 Hz, 1H);APESI+MS m/z 487 (M+1)⁻.

EXAMPLE 212-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(ethylsulfinyl)-pyrazolo[1,5-a]pyridine

In a similar manner as described in Example 7, from2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-7-(ethylthio)pyrazolo[1,5-a]pyridinewas obtained the title compound. ¹H NMR (CDCl₃): δ 1.25 (t, J=7.5 Hz,3H), 3.00 (s, 3H), 3.33–3.45 (m, 2H), 7.05 (d, J=5.5 Hz, 1H), 7.20 (t,J=8.6 Hz, 2H), 7.54–7.59 (m, 3H), 7.67 (dd, J=7.3, 8.8 Hz, 1H), 8.52 (d,J=5.5 Hz, 1H), 8.25 (t, J=8.4 Hz, 1H); APESI+MS m/z 429 (M+1)⁻.

EXAMPLE 222-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-7-(ethylthio)-pyrazolo[1,5-a]pyridine

In a similar manner as described in Example 8, from2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-pyrazolo[1,5-a]pyridineand diethyl disulfide in place of toluenesulfonyl chloride was obtained2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-7-(ethylthio)pyrazolo[1,5-a]pyridine.¹H NMR (CDCl₃): δ 1.46 (t, J=7.4 Hz, 3H), 2.60 (s, 3H), 3.16 (q, J=7.4Hz, 2H), 6.67 (d, J=5.5 Hz, 1H), 6.81 (d, J=7.3 Hz, 1H), 7.13 (t, J=8.6Hz, 2H), 7.35 (t, J=8.1 Hz, 1H), 7.59 (dd, J=5.5, 8.6 Hz, 2H), 8.22 (d,J=5.5 Hz, 1H), 8.28 (d, J=9.0 Hz, 1H).

EXAMPLE 23 Dimethyl2-(4-fluorophenyl)-3-(4-(2-cyclopropylamino)pyrimidinyl)-7-pyrazolo[1,5-a]pyridinylcarboxamide

To a stirred solution of 2-(4-fluorophenyl)-7-pyrazolo[1,5-a]pyridine(5.38 g, 25 mmol) in dry tetrahydrofuran (100 mL) at −78° C. was addedn-butyl lithium (2.5 M in hexanes. 12.2 mL, 30 mmol) and the mixture wasstirred for 20 min. Dimethyl carbamoyl chloride (7.0 mL, 76 mmol) wasadded in one portion and the mixture was allowed to warm to roomtemperature. Diethyl ether was added followed by saturated aqueoussodium bicarbonate solution. The organic phase was separated and driedusing anhydrous sodium sulfate. The drying agent was removed byfiltration and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel chromatography to give dimethyl2-(4-fluorophenyl)-7-pyrazolo[1,5-a]pyridinylcarboxamide as a lightgreen solid, 6.07 g (85%). In a similar manner as described in Example34 from dimethyl2-(4-fluorophenyl)-7-pyrazolo[1,5-a]pyridinylcarboxamide was obtainedthe title compound. ¹H NMR (DMSO-d₆): δ 8.71 (d, 1H, J=8.1 Hz), 8.11 (d,1H, J=5.1 Hz), 7.65 (m, 2H), 7.57 (dd, 1H, J=7.2, 8.7 Hz), 7.44 (d, 1H,J=2.7 Hz), 7.37 (m, 2H), 7.18 (d, 1H, J=6.3 Hz), 6.26 (d, 1H, J=5.1 Hz),3.11 (s, 3H), 2.84 (s, 3H), 2.65 (m, 1H), 0.74 (m, 2H), 0.55 (m, 2H). MS(ES+ve): 417 (87%, M⁺).

EXAMPLE 247-(2-Fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)-pyrimidinyl)-pyrazolo[1,5-a]pyridine

In a similar manner as described in Example 7, from7-(2-fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)pyrazolo[1,5-a]pyridinewas obtained7-(2-fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine.¹H NMR (CDCl₃): δ 3.04 (s, 3H), 4.65 (t, J=4.0 Hz, 1H), 4.75 (t, J=4.0Hz, 1H), 4.91 (t, J=4.1 Hz, 1H), 5.06 (t, J=4.1 Hz, 1H), 6.50 (d, J=7.5Hz, 1H), 7.02 (d, J=5.5 Hz, 1H), 7.24 (t, J=8.6 Hz, 2H), 7.54 (t, J=8.3Hz, 1H), 7.62–7.67 (m, 2H), 8.48–8.53 (m, 2H).

EXAMPLE 252-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)-pyrazolo[1,5-a]pyridine

In a similar manner as described in Example 7, from2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridineand m-chloroperbenzoic acid was obtained2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)-pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine.¹H NMR (CDCl₃): δ 3.03 (s, 3H), 4.85 (q, J=8.0 Hz, 2H), 6.60 (d, J=7.3Hz, 1H), 7.05 (d, J=5.3 Hz, 1H), 7.24 (t, J=7.6 Hz, 2H), 7.52 (t, J=8.2Hz, 2H), 7.60–7.68 (m, 2H), 8.51 (d, J=5.5 Hz, 1H), 8.57 (d, J=8.8 Hz,1H).

EXAMPLE 26 2-(4Fluorophenyl)-3-(4-pyridyl)-pyrazolo[1,5-a]pyridine

a) 2-(4-Fluorophenyl)-3-(4-pyridyl)-pyrazolo[1,5-a]pyridine.

To a solution of 2-(4-fluorophenyl)-3-bromopyrazolo[1,5-a]pyridine (0.2g, 0.68 mmol) and 4-(tributylstannyl)pyridine (0.38 g, 1 mmol) in drytoluene (10 mL) was added tetrakis(triphenylphosphine)palladium (0)(0.03 g, 0.03 mmol) and the mixture was heated at reflux temperatureunder a nitrogen atmosphere for about 48 hours. The mixture was cooledto room temperature and diluted with diethyl ether (40 mL). The mixturewas poured into a 10% aqueous solution of potassium fluoride (20 mL) andthe mixture was stirred for 1 hour. The biphasic mixture was filteredthrough a pad (1 cm) of diatomaceous earth and the Organic phase wasseparated. The aqueous phase was extracted with diethyl ether (10 mL)and the combined organic phases are washed with brine, dried overanhydrous magnesium sulfate, filtered and the solvent evaporated underreduced pressure. The residue was purified using silica gelchromatography with 20% ethyl acetate in hexanes, followed by 50% ethylacetate in hexanes, as eluent to give the title compound as an off whitesolid, 0.16 g (80%). ¹H NMR (CDCl₃) δ 8.58 (br s, 2H), 8.50 (d, 1H,J=7.2 Hz), 7.63 (d, 1H, 9 Hz), 7.52 (m, 2H), 7.27–7.20 (m, 3H), 7.06 (t,2H, 8.7 Hz), 6.86 dt, 1H, J=7, 1 Hz). MS (+ve ion electrospray) 290(100), (MH⁺).

b) 2-(4Fluorophenyl)-3-bromopyrazolo[1,5-a]pyridine.

To a solution of 2-(4fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylicacid (0.96 g, 3.75 mmol) in dry N,N-dimethylformamide (10 mL) was addedsodium bicarbonate (0.95 g, 11.3 mmol) followed by N-bromosuccinimide(0.667 g, 3.75 mmol) and the mixture was stirred at room temperatureunder a nitrogen atmosphere for about 90 minutes. The mixture was pouredinto water (300 mL) and the resulting solid was collected by filtrationand washed with water. The solid was dissolved in 10:1chloroform:methanol (10 mL) and filtered through a pad (0.5 cm) ofsilica gel using 10:1 chloroform:methanol as eluent. The filtrate wasevaporated to leave the title compound as a tan solid, 0.87 g (80%). ¹HNMR (d6 DMSO) δ 8.7 (d, 1H, J=6.9 Hz), 8.02 (dd, 2H, J=8.7, 5.7 Hz),7.61 (d, 1H, J=8.4 Hz), 7.40 (t, 1H, J=6 Hz), 7.38 (t, 2H, J=9 Hz), 7.04(t, 1H, J=6.9 Hz). MS (+ve ion electrospray) 293 (100), (MH⁺).

c) 2-(4-Fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic acid.

A solution of methyl2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylate (5.0 g, 18.5mmol) in 2N aqueous sodium hydroxide (50 ml) and methanol (30 mL)was-heated at reflux for about 3 hours. The mixture was filtered and thefiltrate was washed with diethyl ether (20 mL) and then concentratedunder reduced pressure to about half the original volume. Concentratedhydrochloric acid was added to adjust the pH to about 2 and theresulting solid was collected by filtration and washed with water anddried under vacuum to give the title compound as a white solid, 4.8 g(ca. 100%). ¹H NMR (d6 DMSO) δ 12.43 (br s, 1h), 8.84 (d, 1H, J=6.9 Hz),8.14 (d, 1H, J=9 Hz), 7.82 (m, 2H), 7.57 (t, 1H, J=8.1 Hz), 7.28 (t, 2H,J=9 Hz), 7.15 (td, 1H, J=6.9, 1.2 Hz). MS (+ve ion electrospray) 257(100), (MH⁺).

d) Methyl 2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylate.

A stirred solution of methyl 3-(4-fluorophenyl)propiolate (8.02 g, 45mmol) and 1-aminopyridinium iodide (10 g, 45 mmol) in dry acetonitrile(150 mL) was cooled to about 0° C. A solution of1,8-diazabicycloundec-7-ene (13.7 g, 90 mmol) in dry acetonitrile (50mL) was added dropwise over 1 hour. The mixture was allowed to stir atroom temperature for about 18 h. The reaction mixture was cooled in anice bath for about 30 minutes and the precipitate was collected byfiltration and washed with cold acetonitrile (10 mL). The solid wasdried under reduced pressure to give the title compound as a whitesolid, 8.48 g (70%). ¹H NMR (CDCl3) δ 8.50 (d, 1H, J=8.4 Hz), 8.18 (d,1H, J=8.8 Hz), 7.78 (m, 2H), 7.42 (t, 1H, J=8.4 Hz), 7.13 (t, 2H, J=8.8Hz), 6.97 (td, 1H, J=6.8, 1 Hz).). MS (+ve ion electrospray) 271 (100),(MH⁺).

e) Methyl 3-(4fluorophenyl)propiolate.

A solution of 1-(4-fluorophenyl)-2-trimethylsilylacetylene (64 g, 0.33mol) in dry diethyl ether (400 mL) was cooled to 0° C. under a nitrogenatmosphere. To this solution was added, dropwise over 45 minutes, asolution of tetrabutylammonium fluoride (1M in tetrahydrofuran, 330 mL,0.33 mol) via a dropping funnel maintaining the internal temperaturebelow 2° C. The mixture was allowed to warm to room temperature overabout 1 hour. Diethyl ether (300 mL) was added to the mixture and theorganic solution was washed with water, saturated brine and then driedover anhydrous magnesium sulfate. The magnesium sulfate was removed byfiltration and the filtrate was cooled to about −78° C. n-Butyl lithium(1.6M in hexanes, 450 mL, 0.72 mol) was added dropwise via a droppingfunnel over about 1 hour while the temperature was maintained below −66°C. After complete addition the mixture was stirred at −78° C. for about1 hour and then a precooled solution of methyl chloroformate (110 mL,1.4 mol) in dry diethyl ether (200 mL) was added in a continuous streamas fast as possible. The mixture was allowed to cool to −78° C. and theallowed to warm to room temperature over 1.5 h. The organic reactionmixture was washed with water and saturated brine and then dried overanhydrous magnesium sulfate. The solvents are remove under reducedpressure and the residue dried under reduced pressure to give the titlecompound as a brown solid, 36.5 g (61%). ¹H NMR (CDCl3) δ 7.58 (dd, 2H,J=9, 5.4 Hz), 7.07 (t, 2H, J=8.5 Hz), 3.84 (s, 3H). MS (+ve ionelectrospray) 178 (30), (M⁺).

f) 1-(4-Fluorophenyl)-2-trimethylsilylacetylene.

4-Fluoroiodobenzene (112 mL, 0.97 mol) and triethylamine (176 mL, 1.26mol) are dissolved in dry tetrahydrofuran (1.2 L) and nitrogen gas wasbubbled through the solution for about 20 min. Copper (I) iodide (1.08g, 5.7 mmol) and bis(triphenyphosphine)palladium dichloride (2.15 g, 3mmol) are added and then trimethylsilylacetylene (178 mL, 1.3 mol) wasadded dropwise over about 40 min with the temperature being maintainedat about 23° C. A large amount of precipitate forms (presumably Et₃NHCl)which necessitates mechanical stirring. Following complete addition ofthe trimethylsilylacetylene the mixture was allowed to stir at roomtemperature for about 18 hours. The mixture was filtered and the solidwashed with cyclohexane. The combined filtrates are concentrated underreduce pressure to give a brown oil. Application of this oil to a pad ofsilica gel followed by elution with cyclohexane gave a yellow solution.Removal of the solvent gave the title compound as a yellow oil; 182.8 g(95%).

EXAMPLE 272-(4-Fluorophenyl)-7-methyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine

a) 2-(4-Fluorophenyl)-7-methyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine.

In a similar manner as described in Example 26, from2-(4-fluorophenyl)-3-bromo-7-methylpyrazolo[1,5-a]pyridine (0.1 g, 0.33mmol) and 4-(tri-n-butyl)stannylpyridine (0.17 g, 0.46 mmol) wasobtained the title compound as a white solid, 0.016 g (14%). Thismaterial was dissolved in diethyl ether and treated with HCl in diethylether to afford the corresponding hydrochloride salt. ¹H NMR (DMSO-d6) δ8.74 (d, 2H, J=6.6 Hz), 7.91 (d, 1H, J=8.9 Hz), 7.81 (d, 2H, J=6.6 Hz),7.61 (m, 2H), 7.56 (t, 1H, J=15.9 Hz), 7.34 (t, 2H, J=17.6 Hz), 7.15 (d,1H, J=6.9 Hz), 2.79 (s, 3H). MS (+ve electrospray) 303 (100), (M+).

b) 2-(4-Fluorophenyl)-3-bromo-7-methyl-pyrazolo[1,5-a]pyridine.

Following the procedure outlined in Example 26, from2-(4-fluorophenyl)-7-methyl-pyrazolo[1,5-a]pyridine-3-carboxylic acidwas obtained the title compound, ¹H NMR (CDCl₃) δ 8.00 (m, 2H), 7.38 (d,1H, J=8.8 Hz), 7.11 (m, 3H), 6.62 (d, 1H, J=6.9 Hz), 2.71 (s, 3H). MS(+ve electrospray) 306 (25), (MH+).

c) 2-(4-Fluorophenyl)-7-methyl-pyrazolo[1,5-a]pyridine-3-carboxylicacid.

In a similar manner as described in Example 26, from methyl2-(4-fluorophenyl)-7-methyl-pyrazolo[1,5-a]pyridine-3-carboxylate wasobtained the title compound as a white solid, ¹H NMR (DMSO-d6) δ 8.08(d, 1H, J=8.8 Hz), 7.84 (m, 2H), 7.76 (m, 1H), 7.53 (m, 1H), 7.30 (t,2H, J=17.8 Hz), 7.09 (d, 1H, J=6.8 Hz), 2.75 (s, 3H). MS (+veelectrospray) 270 (100), (M+).

d) Methyl2-(4-fluorophenyl)-7-methyl-pyrazolo[1,5-a]pyridine-3-carboxylate.

To a stirred solution of methyl 3-(4-fluorophenyl)propiolate (3.47 g,19.5 mmol) and 1-amino-2-methylpyridinium2,4,6-trimethylbenzenesulfonate (6.0 g, 19.5 mmol) in dry acetonitrile(75 mL) was added, dropwise over 10 min a solution of1,8-diazabicycloundec-7-ene (5.82 mL, 39 mmol) in dry acetonitrile (25mL). The mixture was allowed to stir at room temperature for about 18hours. The solvent was evaporated under reduced pressure and the residuewas partitioned between water (500 mL) and ethyl acetate (250 mL) andthe organic phase separated. The aqueous was extracted with ethylacetate and the combined organic extracts are dried over anhydrousmagnesium sulfate, and the solvent removed under vacuum. The residue waspurified by chromatography on silica gel using 10:1 hexanes:ethylacetate as eluent to give the title compound as a white solid, 4.65 g(86%). ¹H NMR (CDCl₃) δ 8.15 (d, 1H, J=8.8 Hz), 7.86 (m, 2H), 7.41 (t,1H, J=8.9 Hz), 7.19 (t, 2H, J=17.6 Hz), 6.87 (d, 1H, J=7.0 Hz), 3.89 (s,3H), 2.85 (s, 3H). MS (+ve ion electrospray) 285 (100), (MH+).

e) 1-Amino-2-methylpyridinium 2,4,6-trimethylbenzenesulfonate.

To cold (0° C.) trifluoroacetic acid (50 mL) was addedN-tert-butoxycarbonyl-O-(mesitylsulfonyl)hydroxylamine (16.09 g, 51mmol) in portions over about 15 minutes. The solution was then stirredfor about 15 minutes at room temperature. The solution was poured intoice water (250 mL) and the resulting white precipitate was collected byfiltration and air-dried for 5 minutes. The solid was dissolved inchloroform (100 mL) and this solution was dried over anhydrous magnesiumsulfate. The magnesium sulfate was removed by filtration and thefiltrate was added to a solution of 2-picoline (5.0 g, 54 mmol) inchloroform (5 mL). The mixture was stirred for 45 min and then filtered.To the filtrate was added diethyl ether (225 ml) and the product allowedto precipitate. The solid was collected by filtration, washed withdiethyl ether (50 mL) and dried to give the title compound as a whitesolid, 12.9 g (82%). ¹H NMR (CDCl₃) δ 9.45 (d, 1H), 8.4 (br s, 2H), 7.84(t, 1H), 7.55 (t, 1H), 7.50 (d, 1H), 6.80 (s, 2H), 2.81 (s, 3H), 2.62(s, 6H), 2.25 (s, 3H). MS (+ve electrospray) 109 (100), (M⁺).

EXAMPLE 282-(4-Fluorophenyl)-7-methoxy-3-(4-pyridinyl)pyrazolo[1,5-a]-pyridine

In a similar manner as described in Examples 26 and 27, from2-methoxypyridine was obtained the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ 4.12 (s, 3H), 6.52 (d, 1H, J=7.2 Hz), 7.24 (m, 4H), 7.35 (m,2H), 7.51 (dd, 2H, J=5.6 Hz, 8.8 Hz), 8.53 (d, 2H, J=6.0 Hz). MS (ES+)m/z 320 (M⁺+H).

Alternatively,2-(4-fluorophenyl)-7-methoxy-3-(4pyridinyl)pyrazolo[1,5-a]-pyridine canbe prepared from7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine (seeExample 29) by the following procedure:7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine (0.05g, 0.15 mmol) was added to a solution of sodium methoxide (0.75 mmol) indry methanol (5 mL) and the mixture was heated at reflux for about 24hours. Water was added and the mixture was extracted with ethyl acetate.The combined organic extracts are washed with brine and dried overanhydrous magnesium sulfate. The solution was filtered through a shortpad of silica gel and the solvent was evaporated under vacuum. Theresidue was purified by silica gel chromatography using 1:10 MeOH:Ethylacetate to give the title compound, 0.039 g (80%). ¹H NMR and MS areidentical to those described above.

EXAMPLE 297-Chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]-pyridine

A stirred solution of2-(4-fluorophenyl)-3-(4-pyridinyl)-pyrazolo[1,5-a]pyridine (from Example26, 100 mg, 0.346 mmol) in dry tetrahydrofuran (4 mL) was cooled toabout −78° C. under N₂ and n-butyllithium in hexanes (2.5 M in hexanes,0.27 mL, 0.7 mmol) was added dropwise. The mixture was stirred at −78°C. for about 30 min and a solution of p-toluenesulfonyl chloride (0.15g, 0.76 mmol) in dry tetrahydrofuran (1 mL) was added. The mixture wasallowed to warm to room temperature over 30 min and was stirred at roomtemperature for 1 hour. Water was added and the mixture was poured intoa separatory funnel. The organic layer was separated, and the aqueouslayer was extracted with ethyl acetate. The combined organic layers weredried using anhydrous magnesium sulfate, filtered and evaporated.Purification by silica gel chromatography yielded the title compound,0.087 g (78.6%). ¹H NMR (CDCl₃): δ 8.65 (d, 2H, J=5.8 Hz), 7.55–7.69 (m,3H), 7.30 (d, 2H, J=5.8 Hz), 7.11–7.21 (m, 1H), 7.04–7.13 (m, 3H). MS(ES+ve): 326 (25, M+3), 323 (50, M⁺), 290 (100).

EXAMPLE 302-(4-Fluorophenyl)-3-(2-fluoro-4-pyridinyl)-7-methoxypyrazolo[1,5-a]pyridine

A solution of3-bromo-2-(4-fluorophenyl)-7-methoxypyrazolo[1,5-a]pyridine (fromExample 27, 180 mg, 0.560 mmol), 2-fluoropyridin-4-ylboronic acid (fromExample 33, 112 mg, 0.800 mmol) anddichlorobis(triphenylphosphine)palladium (40.0 mg, 0.056 mmol) inN,N-dimethylformamide (6.00 mL) was placed in a pre-heated oil bath at110° C. To the reaction was added, in a dropwise manner, 2M sodiumcarbonate (0.840 mL, 1.68 mmol). The reaction was allowed to stir forthree hours before cooling to room temperature and filtering through aCelite 545 pad. The Celite filter was washed with ethyl acetate and thefiltrate was concentrated to dryness at 50° C. under vacuum. The residuewas dissolved in methylene chloride and dried over anhydrous magnesiumsulfate. The drying agent was removed by filtration and the filtrate wasconcentrated and purified by silica gel chromatography to yield thetitle compound (110 mg, 0.326 mmol, 58%). ¹H NMR (CDCl₃): δ 8.14 (d, 1H,J=5.5 Hz), 7.53(dd, 2H, J=6.0, 8.0 Hz), 7.24–7.32(m, 2H), 7.00–7.10(m,3H), 6.89(s, 1H), 6.23(dd, 1H, J=2.0, 6.0 Hz), 4.2(s, 3H). MS (ES+ve):338.1 (40, M⁺), 323.1 (100).

EXAMPLE 31N-Butyl-4-[2-(4-fluorophenyl)-7-methoxypyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine

In a sealed-tube was combined2-(4Fluorophenyl)-3-(2-fluoro-4-pyridinyl)-7-methoxypyrazolo[1,5-a]pyridine(from Example 30, 20 mg, 0.06 mmol) and n-butylamine (2.0 mL, 1.5 g, 20mmol), and the reaction was placed in a pre-heated oil bath at 130° C.The reaction was stirred at 130° C. until consumption of startingmaterial was indicated by TLC analysis (50% ethyl acetate in hexanes).The contents of the sealed-tube was transferred to a flask andconcentrated to dryness at 50° C. under high vacuum. The residue waspurified by silica gel chromatography to yield the title compound, 2.0mg (0.005 mmol, 80%). ¹H NMR (d₆-acetone): δ 8.04(d, 1H, J=5.1 Hz),7.74(dd, 2H, J=5.7, 9.0 Hz), 7.33–7.38(m, 2H), 7.22(t, 2H, J=9.0 Hz),6.45–6.54(m, 3H), 4.25(s, 3H), 3.30–3.40(m, 2H), 1.60(quint, 2H, J=7.2Hz), 1.45(sext, 2H, J=7.2 Hz), 0.9(t, 3H, J=7.2 Hz). MS (ES+ve): 391.1(100, M⁺), 376.3 (100).

EXAMPLE 32N-{4-[5-Chloro-7-(ethylsulfanyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine

a) 2-(4-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone.

To a cold (0° C.) solution of 4-chloro-2-picoline (5.0 g, 39 mmol) andethyl 4-fluorobenzoate (6.6 g, 39 mmol) in tetrahydrofuran (100 mL) wasadded lithium bis(trimethylsilyl)amide (80 mL, 1.0 M in tetrahydrofuran,80 mmol) dropwise via a pressure equalizing funnel over 30 minutes. Uponcomplete addition, the cold bath was removed and the resulting solutionwas stirred at room temperature for 15 hours. The reaction mixture wasconcentrated under reduced pressure and methanol was added to thereaction, resulting in the formation of a white precipitate. Theprecipitate was collected by filtration and dried to give2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (9.6 g, 99%) as awhite solid. ¹H-NMR (DMSO-d₆): δ 7.90 (m, 3H), 7.11 (t, 2H), 6.56 (s,1H), 5.67 (s, 1H), 4.14 (m, 2H); ¹⁹F-NMR (DMSO-d₆): δ 115.67; MS m/z 250(M+1).

b) 2-(4-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime.

To a solution of 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone(9.6 g, 38 mmol) in methanol (200 mL) was added hydroxylaminehydrochloride (13.5 g, 190 mmol) followed by the addition of a sodiumhydroxide solution (7.8 g, 190 mmol in 50 mL of water). The resultingsuspension was heated at reflux for 2 hours and then allowed to cool toroom temperature. The mixture was concentrated and water was added tothe resulting slurry. A white precipitate formed, which was collected byfiltration, washed with water and dried (magnesium sulfate) to give2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (8.45 g, 84%)as a white solid. ¹H-NMR (DMSO-d₆): δ 11.56 (s, ₁H), 8.44 (d, ₁H), 7.80(m, 2H), 7.40 (m, 2H), 7.22 (m, 2H), 4.29 (s, 2H); ¹⁹F-NMR (DMSO-d₆): δ113.44; MS m/z 265 (M+1).

c) 5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine.

To a solution of 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanoneoxime (8.0 g, 30 mmol) in 1,2-dimethoxyethane (50 mL) at 0° C. was addedtrifluoroaceticanhydride (6.3 g, 30 mmol), keeping the temperature below10° C. during the addition. After the addition was complete, thereaction was warmed to room temperature. The solution was then cooled to4° C. and a solution of triethylamine (8.4 mL, 60 mmol) in1,2-dimethoxyethane (20 mL) was added over a period of 0.5 hours. Themixture was allowed to warm to room temperature and was stirred for 1.5hours. To this mixture was added iron(II) chloride (40 mg) and thereaction was heated at 75° C. for 15 hours. The reaction mixture waspoured into water (300 mL). The resulting suspension was extracted withethyl acetate. The combined organics were dried (magnesium sulfate),filtered and concentrated to a solid residue. This residue was purifiedby flash chromatography (1:1 ethyl acetate-hexane) to give5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (4.2 g, 57%) as awhite solid. ¹H-NMR (CDCl₃): δ 8.36 (d, 1H), 7.93 (q, 2H), 7.49 (d, 1H),7.15 (t, 2H), 6.70 (dd, 1H), 6.69 (s, 1H); ¹⁹F-NMR (CDCl₃): δ 113.30; MSm/z 247 (M+1).

d) 5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde.

Phosphorous oxychloride (0.6 mL, 6.4 mmol) was added toN,N-dimethylformamide (10 mL) and the resulting mixture stirred at roomtemperature for 10 minutes.5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (1.0 g, 4.1 mmol) wasadded and the reaction mixture was stirred at room temperature for 12hours. The reaction mixture was poured into ice-water and neutralized topH 7 with aquous ammonium hydroxide. The resulting slurry was extractedwith dichloromethane (3×40 mL). The combined organics were washed withbrine, dried (magnesium sulfate), filtered and concentrated to give,after recrystallization from acetonitrile,5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (0.95g, 85%) as a white solid. ¹H-NMR (CDCl₃): δ10.07 (s, 1H), 8.49 (d, 1H),8.44 (d, 1H), 7.78 (q, 2H), 7.22 (t, 2H), 7.07 (dd, 1H); MS m/z 275(M+1).

e)1-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-one.

To a solution of5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (0.93g, 3.4 mmol) in tetrahydrofuran (20 mL) at −78° C. was addedethynylmagnesium bromide (16 mL, 0.5 M in tetrahydrofuran, 8.0 mmol).The mixture was allowed to warm to room temperature and stirred for 1hour. Water was added to the reaction and the resulting mixture wasextracted with ethyl acetate. The ethyl acetate phase was dried(magnesium sulfate), filtered and concentrated to a solid residue. Thisresidue was dissolved in dichloromethane (50 mL) and manganese dioxide(5 g) was added. This slurry was stirred at room temperature for 2hours. The manganese dioxide was removed by filtration and the filtratewas concentrated to a solid. This solid was purified by flashchromatography (dichloromethane) to give1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-one(0.63 g, 62% for two steps) as a white solid. ¹H-NMR (CDCl₃): δ 8.52 (d,1H), 8.47 (d, 1H), 7.69 (q, 2H), 7.18 (t, 2H), 7.07 (dd, 1H), 3.00 (s,1H); ¹⁹F-NMR (CDCl₃): δ 111.69; MS m/z 299 (M+1).

f)4-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine.

To a solution of1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-one(0.61 g, 2.0 mmol) in N,N-dimethylformamide was added cyclopentylguanidine hydrochloride (0.67 g, 4.1 mmol) followed by anhydrouspotassium carbonate (0.57 g, 4.1 mmol). The resulting mixture was heatedat 80° C. for 12 hours. Upon cooling to room temperature, water wasadded. The mixture was extracted with ethyl acetate. The ethyl acetatephase was washed with brine, dried (magnesium sulfate), filtered andconcentrated in vacuo. The resulting residue was purified by flashchromatography (1:1 ethyl acetate-hexane) to give, afterrecrystallization from acetonitrile,4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.6 g, 74%) as a white solid. ¹H-NMR (CDCl₃): δ8.54 (broad s, 1H), 8.40(d, 1H), 8.04 (d, 1H), 7.60 (q, 2H), 7.16 (t, 2H), 6.88 (dd, 1H), 6.28(d, 1H), 5.22 (d, 1H), 4.40 (m, 1H), 1.4–2.2 (m, 8H); ¹⁹F-NMR (CDCl₃): δ112.5; MS m/z 408 (M+1).

g)N-{4-[5-Chloro-7-(ethylsulfanyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine.

To a solution of4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(150 mg, 0.37 mmol) in anhydrous tetrahydrofuran (5 mL) at −78° C. wasadded n-butyllithium (0.7 mL, 1.1 mmol of 1.6 M solution in hexane). Theresulting solution was stirred for 10 minutes at −78° C., followed byaddition of diethyldisulfide (0.14 mL, 1.1 mmol). The reaction wasstirred at −78° C. for 20 minutes and then allowed to warm to roomtemperature. Water and ethyl acetate were added to the reaction mixture.The phases were separated, the aqueous phase washed with ethyl acetateand the combined organic phase dried (magnesium sulfate), filtered andconcentrated in vacuo. The resulting solid was purified by flashchromatography (1:1 ethyl acetate-hexane) to give, afterrecrystallization from ethyl acetateN-{4-[5-chloro-7-(ethylsulfanyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine(90 mg, 52%) as a solid. ¹H-NMR (CDCl₃): δ 8.42(broad s, 1H), 8.08 (d,1H), 7.66 (q, 2H), 7.17 (t, 2H), 6.73 (d, 1H), 6.31 (d, 1H), 5.18 (d,1H), 4.20 (m, 1H), 3.22 (q, 2H), 2.0–2.1 (m, 2H), 1.4–1.9 (m, 9H);¹⁹F-NMR (CDCl₃): δ 112.8; MS m/z 468 (M+1).

EXAMPLE 33 2-Fluoropyridin-4-ylboronic acid

To a stirred solution of n-butyl lithium (3.2 mL, 2.5M, 8.0 mmol) in drydiethyl ether (20 mL) at −78° C. was added a solution of2-fluoro-4-iodopyridine (1.5 g, 6.7 mmol) in dry ether (10 mL) and thereaction mixture was stirred at −78° C. for 10 minutes. Tributyl borate(2.4 mL, 2.01 g, 8.7 mmol) was added and the reaction mixture wasallowed to stir to room temperature over 2 hours. Water (5 mL) was addedfollowed by 2N aqueous sodium hydroxide solution (10 mL) to sissolve thesolids. The organic phase was separated. The aqueous phase was acidifiedto pH3 using 6N HCl and the resulting white solid was collected byfiltration and dried under vacuum to give the title compound, 0.74 g(78%). 1H NMR (DMSO-d6) δ 8.65 (br s, 2H), 8.21 (d, 1H, J=4.8 Hz), 7.59(t, 1H, J=4.8 Hz), 7.37 (d, 1H, J=1.8 Hz).

EXAMPLE 34 Ethyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylate

a) 1-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone.

To a solution of 4-fluoroacetophenone (13.8 g, 0.100 mol) and2-chloro-5-trifluoromethylpyridine (20.0 g, 0.110 mol) intetrahydrofuran (400 mL) was added sodium hydride (95%, 5.56 g, 0.220mol) in several portions. The reaction was stirred at room temperaturefor 72 hours then carefully quenched by the addition of water (300 mL)and diethyl ether (200 mL). The organic layer was separated andextracted with 6N HCl (2×300 mL). The aqueous extracts were cooled to 0°C. and 6N NaOH was used to adjust the solution to pH12. The mixture wasthen extracted with diethyl ether and the combined organic extracts weredried over magnesium sulfate. The drying agent was removed by filtrationand the filtrate was evaporated to dryness to afford the title compoundas a tautomeric mixture, 20.9 g (73%). ¹H NMR (CDCl₃): δ 8.87(s),8.63(s), 8.14(dd, J=5.1, 8.4 Hz), 8.00–7.83(m), 7.51(d, J=8.4 Hz),7.22–7.12(m), 6.13(s), 4.60(s). MS (ES): 284 (M+1).

b) 1-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone oxime.

To a solution of1-(4-fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone (80.0 g,0.282 mol) in methanol (1 L) at room temperature was added 10% aqueoussodium hydroxide (436 mL, 1.09 mol). The resulting solution was stirredvigorously as solid hydroxylamine hydrochloride (98.0 g, 1.40 mol) wasadded. The mixture was heated to reflux for 2 hours, treated withdecolorizing charcoal while hot, then filtered through Celite while hot.The filtrate was concentrated to one-half its original volume and thencooled to 0° C. with stirring for one hour. The resulting solids werecollected by filtration, washed with water, and dried under vacuum at50° C. overnight to provide the title compound as a light yellow powder,73.9 g (88%). ¹H NMR (DMSO-d₆): δ 11.60(s, 1H), 8.86(s, 1H), 8.14(dd,1H, J=2.1, 8.1 Hz), 7.78(dd, 2H, J=5.7, 9.0 Hz), 7.53(d, 1H, J=8.4 Hz),7.23(t, 2H, J=9.0 Hz), 4.40(s, 2H). MS (ES): 299 (M+1).

c) 3-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)-2H-azirine.

To a solution of1-(4-fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone oxime (25.0g, 0.084 mol) in methylene chloride (400 mL) was added triethylamine(46.7 mL, 0.335 mol). The solution was cooled to 0° C. under a nitrogenatmosphere, and trifluoroacetic anhydride (14.1 mL, 0.100 mol) was addeddropwise. The reaction was stirred for 0.5 hours then quenched withwater. The organic layer was separated and dried over anhydrousmagnesium sulfate. The drying agent was removed by filtration and thesolvent was evaporated from the filtrate to leave an oil. The residuewas loaded onto a silica gel column and eluted with 15% ethyl acetate inhexanes to give the title compound as an oil which solidified onstanding, 19.4 g (82%). ¹H NMR (CDCl₃): δ 8.76(s, 1H), 7.93(dd, 2H,J=5.4, 8.7 Hz), 7.83(dd, 1H, J=2.1, 8.4 Hz), 7.27(t, 2H, J=8.7 Hz),7.21(d, 1H. J=8.1 Hz), 3.54 (s, 1H). MS (ES): 281 (M+1).

d) 2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine.

3-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)-2H-azirine (40.0 g,0.143 mol) was dissolved in 1,2,4-trichlorobenzene (400 mL) and themixture was heated to 200° C. for 10 hours. The reaction mixture wasthen cooled to room temperature and poured onto a silica gel column. Thecolumn was eluted with hexanes to remove the 1,2,4-trichlorobenzene; andthen with 20% diethyl ether in hexanes to elute the product. The desiredfractions were combined and the solvent was evaporated under reducedpressure to leave the title compound, 28.7 g (71%). ¹H NMR (CDCl₃): δ8.84(s, 1H), 7.98(dd, 2H, J=5.4, 8.7 Hz), 7.65(d, 1H, J=9.3 Hz), 7.28(d,1H, J=9.3 Hz), 7.20(t, 2H, J=8.7 Hz), 6.88(s, 1H). MS (ES): 281 (M+1).

e)2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde.

To a cold (0° C.) solution of phosphorus oxychloride (8.0 mL, 86 mmol)in N,N-dimethylformamide (160 mL) was added2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo-[1,5-a]pyridine (11.0 g,39.3 mmol). The reaction mixture was stirred at room temperature for 72hours, then quenched with ice water. The solid precipitate was collectedon a filter to provide2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde(11.4 g, 94%) as a white solid. R_(f) 0.45 (4:1 hexanes:ethyl acetate);¹H NMR (400 MHz, CDCl₃) δ 10.15 (s, 1H), 8.92 (s, 1H), 8.53 (d, 1H),7.80 (m, 2H), 7.70 (d, 1H), 7.27 (t, 2H); ¹⁹F NMR (CDCl₃) δ −62.62,−110.62; MS m/z 307 (M−1).

f)1-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol.

To a cold (−78° C.) suspension of2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde(11.4 g, 37.0 mmol) in tetrahydrofuran (100 mL) was addedethynylmagnesium bromide (111 mL, 0.5 M in tetrahydrofuran, 56 mmol).The reaction mixture was warmed to room temperature and stirred for 14hours. The reaction mixture was poured into water and adjusted toneutral pH with 1N aqueous hydrochloric acid. The aqueous mixture wasextracted with ethyl acetate. The combined extracts were washed withwater and brine. The organic layer was dried over magnesium sulfate.Filtration and concentration provided1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(11.9 g, 96%) as a tan solid. R_(f) 0.18 (4:1 hexanes:ethyl acetate); ¹HNMR (300 MHz, CDCl₃) δ 8.81 (s, 1H), 8.15 (d, 1H), 7.75 (m, 2H), 7.35(d, 1H), 7.19 (t, 2H), 5.76 (s, 1H), 2.71 (d, 1H), 2.60 (d, 1H); MS m/z335 (M+1).

g)1-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one.

To a cold (0° C.) solution of1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(5.00 g, 15.0 mmol) in chloroform (400 mL) was added manganese dioxide(130 g, 1.50 mol). The reaction mixture was stirred at 0° C. for 1.5hours. The reaction mixture was filtered through a pad of Celite. Thefiltrate was concentrated in vacuo to provide1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo-[1,5-a]pyridin-3-yl]-2-propyn-1-one(3.44 g, 69%) as a clear oil. R_(f) 0.39 (4:1 hexanes:ethyl acetate); ¹HNMR (400 MHz, CDCl₃) δ 8.90 (s, 1H), 8.61 (d, 1H), 7.72–7.69 (m, 3H),7.17 (m, 2H), 3.06 (s, 1H); MS m/z 333 (M+1).

h)N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine.

To a suspension of N-cyclopentylguanidine hydrochloride (2.20 g, 13.5mmol) in ethanol (70 mL) was added sodium ethoxide (4.5 mL, 3 M inethanol, 14 mmol). The mixture was stirred at room temperature for 30minutes, then cooled to 0° C. To this mixture was added1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(3.44 g, 10.4 mmol) portionwise. The reaction mixture was stirred at 0°C. for 30 minutes, followed by room temperature for 15 hours. Thereaction mixture was diluted with water (400 mL). The solid precipitatewas collected on a filter to provideN-cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(4.48 g 98%) as an orange solid. ¹H NMR (400 MHz, CDCl₃) δ 8.84 (s, 1H),8.51 (d, 1H), 8.11 (d, 1H), 7.64 (dd, 2H), 7.44 (dd, 1H), 7.17 (t, 2H),6.33 (d, 1H), 5.17 (d, 1H), 4.34 (m, 1H), 2.15–2.06 (m, 2H), 1.84–1.52(m, 6H); ¹⁹F NMR (CDCl₃): δ −62.70, −112.25 MS m/z 442 (M+1); mp155–156° C.

Alternatively,N-cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinaminefrom 2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine maybe synthisized through the following steps.

aa)1-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone.

To a mixture of2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine (10.30 g,36.76 mmol) and acetic anhydride (100 mL) was added conc. sulfuric acid(10 drops) and the mixture was stirred and heated at reflux for 1 hour.The reaction mixture was cooled to room temperature and poured into icewater (300 mL). 2N Aqueous sodium hydroxide solution was added to raisethe pH of the solution to about 10 and the resulting orange precipitatewas collected by filtration. The solid was washed with water, air-dried,and then dried under vacuum to afford the title compound as an orangesolid, 11.87 g (quant.). ¹H NMR (DMSO-d₆): δ 9.58 (s, 1H), 8.41 (d, 1H,J=9.3 Hz), 7.89 (d, 1H, J=9.5 Hz), 7.74 (m, 2H), 7.39 (m, 2H), 2.22 (s,3H). MS (ES) 323 (M+1).

bb)(2E)-3-(Dimethylamino)-1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo-[1,5-a]pyridin-3-yl]-2-propen-1-one.

A mixture of1-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(11.85 g), 36.77 mmol) and N,N-dimethylformamide dimethyl acetal (100mL) was stirred at reflux for 17 hours. The mixture was cooled to roomtemperature and then to 0° C. The resulting orange precipitate wascollected by filtration, washed with cold hexanes, and dried undervacuum to afford the title compound as an orange solid, 10.17 g (73%).¹H NMR (DMSO-d₆): δ 9.44 (s, 1H), 8.22 (d, 1H, J=9.4 Hz), 7.75 (m, 2H),7.65 (d, 1H, J=9.5 Hz), 7.56 (d, 1H, J=12.4 Hz), 7.35 (m, 2H), 5.05 (d,1H, J=12.3 Hz), 3.04 (s, 3H), 2.56 (s, 3H). MS (+ve ion electrospray)377 (80), (M+).

cc)N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine.

To a solution of(2E)-3-(dimethylamino)-1-[2-(4-fluorophenyl)-6-(trifluoromethyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-propen-1-one(314 mg, 0.83 mmol)) in 1-methyl-2-pyrrolidinone (3 mL) was addedN-cyclopentylguanidine hydrochloride (271 mg, 1.66 mmol) and potassiumcarbonate (229 mg, 1.66 mmol). The mixture was heated at 140° C. for 8hours. Upon cooling to room temperature, ether was added followed bywater. The organics were washed with brine, and the aqueous layer wasextracted with ether. The combined organics were dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash chromatography on silica (4:1 hexanes-ethyl acetate) to giveN-cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(204 mg, 56%) as a white solid. ¹ H NMR (CDCl₃): δ 8.84 (s, 1 H), 8.51(d, 1 H), 8.11 (d, 1 H), 7.64 (dd, 2 H), 7.44 (dd, 1 H), 7.17 (t, 2 H),6.33 (d, 1H), 5.17 (d, 1H), 4.34 (m, 1H), 2.15–2.06 (m, 2 H), 1.84–1.52(m, 6 H); ¹⁹F NMR (CDCl₃): δ −62.70, −112.25; MS m/z 442 (M+1); mp155–156° C.

i)N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine.

To a dry round bottom flask was added sodium metal (1.9 g, 83 mmol).Ethanol (110 mL) was added and allowed to react with sodium at roomtemperature until completely dissolved.N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(4.48 g, 10.1 mmol) was added and the reaction mixture was stirred at60° C. for 18 hours. The reaction mixture was cooled and concentrated invacuo to approximately one-fourth of the original volume. The resultingmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with water and brine, then dried over magnesiumsulfate. Filtration and concentration providedN-cyclopentyl-4-[2-(4-fluorophenyl)-6-(triethoxymethyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(4.86 g, 92%) as an off-white solid. R_(f) 0.15 (4:1 hexanes:ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ 8.81 (s, ₁H), 8.39 (d, ₁H), 8.06 (d,1H), 7.62 (m, 2H), 7.47 (d, ₁H), 7.14 (t, 2H), 6.32 (d, 1H), 5.12 (d,1H), 4.35 (m, 1H), 3.43 (q, 6H), 2.08 (m, 2H), 1.80–1.51 (m, 6H), 1.21(t, 9H); MS m/z 520 (M+1).

j)4-[7-Chloro-2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine.

To a cold (0° C.) solution of diisopropylamine (4.1 mL, 29 mmol) intetrahydrofuran (25 mL) was added butyllithium (17 mL, 1.6 M in hexanes,28 mmol) dropwise. The resultant solution was stirred at 0° C. for 10minutes then cooled to −78° C. The reaction mixture was transferred viasyringe to a cold (−78° C.) solution ofN-cyclopentyl-4-[2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(4.86 g, 9.35 mmol) in tetrahydrofuran (25 mL). The reaction mixture wasstirred at −78° C. for 30 minutes. Carbon tetrachloride (3.6 mL, 37mmol) was added and the resulting mixture was warmed to room temperatureand stirred for 2 hours. The reaction mixture was poured onto ice. Afterthe ice had melted, the aqueous mixture was extracted with ethylacetate. The organic layer was washed with water and brine, then driedover sodium sulfate. Filtration and concentration followed by flashchromatography (4:1 hexanes:ethyl acetate) provided4-[7-chloro-2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(2.37 g, 46%) as a yellow solid. R_(f) 0.36 (4:1 hexanes:ethyl acetate);¹H NMR (400 MHz, CDCl₃) δ 8.36 (d, 1H), 8.08 (d, 1H), 7.85 (d, 1H), 7.67(m, 2H), 7.15 (t, 2H), 6.33 (d, 1H), 5.15 (d, 1H), 4.36 (m, 1H), 3.46(q, 6H), 2.10 (m, 2H), 1.81–1.53 (m, 6H), 1.26 (t, 9H); MS m/z 554(M+1).

k) Ethyl7-chloro-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-6-carboxylate.

To a solution of4-[7-chloro-2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(375 mg, 0.677 mmol) in acetone (8 mL) and water (2 mL) was addedp-toluenesulfonic acid monohydrate (321 mg, 1.69 mmol). The reactionmixture was stirred at room temperature for 2 hours, then quenched withice water. The reaction mixture was neutralized with saturated aqueoussodium bicarbonate solution, then concentrated in vacuo to remove themajority of the acetone. The resultant mixture was extracted with ethylacetate. The organic layer was washed with water and brine, then driedover magnesium sulfate. Filtration and concentration, followed by flashchromatography (29:1 dichloromethane:methanol) provided ethyl7-chloro-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylate(175 mg, 54%) as a brown solid. R_(f) 0.08 (29:1dichloromethane:methanol); ¹H NMR (400 MHz, CDCl₃) δ 8.36 (d, 1H), 8.09(d, 1H), 7.82 (d, 1H), 7.65 (m, 2H), 7.14 (t, 2H), 6.30 (d, 1H), 5.19(d, 1H), 4.46 (q, 2H), 4.32 (m, 1H), 2.06 (m, 2H), 1.77–1.21 (m, 9H); MSm/z 480 (M+1).

l) Ethyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylate.

To a solution of ethyl7-chloro-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylate(90 mg, 0.19 mmol) in tetrahydrofuran (1 mL) was added dimethylzinc (281μL, 2.0 M in toluene, 0.56 mmol) andtetrakis(triphenylphosphine)palladium (21 mg, 0.018 mmol). The reactionmixture was stirred at 60° C. for 16 hours. The reaction mixture wasquenched with ice water then extracted with ethyl acetate. The organiclayer was washed with water and brine, then dried over magnesiumsulfate. Filtration and concentration, followed by flash chromatography(49:1 dichloromethane:methanol) provided ethyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylate(40 mg, 45%). ¹H NMR (300 MHz, CDCl₃) δ 8.34 (d, 1H), 8.11 (d, 1H), 7.91(d, 1H), 7.70 (m, 2H), 7.19 (t, 2H), 6.36 (d, 1H), 5.33 (br, 1H), 4.47(q, 2H), 4.38 (m, 1H), 3.26 (s, 3H), 2.12 (m, 2H), 1.83–1.43 (m, 9H); MSm/z 460 (M+1).

EXAMPLE 353-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylicAcid

To a solution of ethyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylate(40 mg, 0.087 mmol) in dioxane (600 μL) was added lithium hydroxide (300μL, 1M aqueous, 0.30 mmol). The reaction mixture was stirred at roomtemperature 16 hours. The reaction mixture was concentrated in vacuo toremove dioxane, then diluted with water. The aqueous mixture wasacidified with 1 N aqueous hydrochloric acid. Upon standing for 72hours, a solid precipitate had formed which was collected by filtrationto provide3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylicacid (31 mg, 82%). R_(f) 0.10 (19:1 dichloromethane:methanol); MS m/z432 (M+1).

EXAMPLE 363-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxamide

Thionyl chloride (200 μL, 2.7 mmol) was added to3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylicacid (31 mg, 0.072 mmol) which had been pre-cooled to 0° C. The reactionmixture was stirred at room temperature for 1 hour. The excess thionylchloride was removed in vacuo. To a solution of the residue indichloromethane (300 μL) was added cyclopropylamine (50 uL, 0.72 mmol).The reaction mixture was stirred at room temperature for 30 minutes. Theresultant mixture was quenched with water and diluted with ethylacetate. Saturated aqueous sodium bicarbonate solution was added to thebiphasic mixture. The organic layer was washed with water and brine,then dried over magnesium sulfate. Filtration and concentration,followed by flash chromatography (3:2 hexanes:ethyl acetate to 2:3hexanes:ethyl acetate) provided3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxamide(15 mg, 44%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (d,1H), 8.05 (d, 1H), 7.62 (m, 2H), 7.30 (d, 1H), 7.13 (t, 2H), 6.29 (d,1H), 5.10 (d, 1H), 4.30 (m, 1H), 2.96 (s, 3H), 2.94 (m, 1H), 2.05 (m,2H), 1.76–1.50 (m, 6H), 0.92 (m, 2H), 0.66 (m, 2H); MS m/z 471 (M+1).

EXAMPLE 37N-Butyl-4-[7-butyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

a) 2-(6-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone.

To a cold (0° C.) solution of 6-chloro-2-picoline (21.4 mL, 196.0 mmol)and ethyl 4-fluorobenzoate (57.5 mL 391.2 mmol) in tetrahydrofuran (311mL) was added lithium bis(trimethylsilyl)amide (391 mL, 1.0 M intetrahydrofuran, 391.0 mmol) dropwise via a pressure equalizing funnelover 1 hour. Upon complete addition, the cold bath was removed and theresultant solution was heated to 45° C. for 15 hours. The mixture wascooled to room temperature and quenched by the addition of water. Etherwas added and the organic layer was washed with brine. The aqueous layerwas extracted with ether and the combined organics were dried overmagnesium sulfate. Filtration and concentration gave a solid residuewhich was purified by recrystallization from ethyl acetate-hexanes toprovide 2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (32.2 g,66%) as a tinted off-white solid existing as a keto-enol tautomericmixture. ¹H NMR (CDCl₃): for the keto tautomer δ 8.11 (m, 2 H), 7.66 (t,1 H), 7.30–7.25 (m 2 H), 7.17 (t, 2 H), 4.48 (s 2 H), ¹⁹F NMR (CDCl₃) δ−104.72 (keto), −111.64 (enol); MS m/z 250 (M+1).

b) 2-(6-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime.

To a solution of 2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone(74.9 g, 299.8 mmol) in methanol (900 mL) was added hydroxylaminehydrochloride (104 g, 1.49 mol) followed by sodium hydroxide (600 mL,10% aqueous, 1.5 mol). The resultant suspension was heated to reflux for2 hours and then cooled to room temperature. The mixture wasconcentrated in vacuo and the residue taken up in ether and water. Theorganic layer was washed with brine. The aqueous layer was extractedwith ether and the combined organics were dried over magnesium sulfate.Filtration and concentration gave a solid residue which was purified byrecrystallization from ethyl acetate-hexanes to provide2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (67.9 g, 86%)as a white solid. ¹H NMR (CDCl₃): δ 8.69 (s, 1 H), 7.71 (dd, 2 H), 7.53(t, 1 H), 7.18–7.16 (m, 2 H), 7.03 (t, 2 H), 4.37 (s, 2 H); ¹⁹F NMR(CDCl₃) δ −111.77; MS m/z 265 (M+1).

c) 7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine.

To a solution of 2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanoneoxime (109.2 g, 414 mmol) in 1,2-dimethoxyethane (500 mL) at 0° C. wasadded trifluoroacetic anhydride (59 mL, 414 mmol), keeping thetemperature below 10° C. After the addition was complete, the reactionwas warmed to 15° C. The solution was then cooled to 4° C. and asolution of triethylamine (116 mL, 828 mmol) in 1,2-dimethoxyethane (60mL) was added over 0.5 hours. After warming to room temperature, themixture was stirred for 1.5 hours. To this was added iron(II) chloride(0.52 g, 4.1 mmol) and the reaction was heated to reflux for 3 hours.The reaction was concentrated and the resulting solid was recrystallizedfrom ethyl acetate-hexanes to give7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (69.7 g, 68%) asoff-white needles. ¹H NMR (CDCl₃): δ 8.03 (m, 2 H), 7.54 (d, 1 H), 7.16(m, 3 H), 6.93 (d, 1 H), 6.91 (s, 1 H); MS m/z 247 (M+1); mp 156–157° C.

d) 7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde.

N,N-Dimethylformamide (100 mL) was cooled to 0° C. and treated withphosphorous oxychloride (5.7 mL, 60.8 mmol). After the addition wascomplete, the mixture was warmed to room temperature and stirred for 1hour. To this was added7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (10.0 g, 40.5 mmol)and the resultant solution was stirred overnight. Water was added,followed by dichloromethane. The aqueous layer was extracted withdichloromethane. The combined organics were washed with brine, driedover magnesium sulfate, filtered and concentrated. The residue wasrecrystallized from diethyl ether and hexanes to give7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (10.6g, 95%) as a fluffy white solid. ¹H NMR (CDCl₃): δ 10.07 (s, 1 H), 8.37(d, 1 H), 7.78 (m, 2 H), 7.48 (t, 1 H), 7.20 (m, 3 H); ¹⁹F NMR (CDCl₃) δ−111.25; MS m/z 275 (M+1); Anal. Calcd for C₁₄H₈ClFN₂O: C, 61.22; H,2.94; N, 10.20. Found: C, 61.34; H, 2.90; N, 10.15; mp 212–213° C.(decomp.).

e)1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol.

In a similar manner as described in Example 34 from7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (5.49g, 20.0 mmol) and ethynylmagnesium bromide (100 mL, 0.5 M intetrahydrofuran, 50.0 mmol) at 0° C., recrystallized fromdichloromethane, was obtained1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(5.3 g, 88%) as a pale yellow crystalline solid. ¹H NMR (CDCl₃): δ 8.04(d, 1H), 7.79 (m, 2H), 7.20 (m, 3H), 7.01 (d, 1H), 5.77 (m, 1H), 2.69(d, 1H), 2.32 (d, 1H); MS m/z 301 (M+1).

f)1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one.

In a similar manner as described in Example 34, from1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(5.30 g, 17.6 mmol) was obtained1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(4.04 g, 77%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.45 (d, 1H), 7.67(m, 2H), 7.50 (t, 1H), 7.19 (d, 1H), 7.12 (t, 2H), 2.93 (s, 1H); MS m/z299 (M+1).

g)N-Butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine.

In a similar manner as described in Example 34 from1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(0.50 g, 1.7 mmol), N-butylguanidine sulfate and sodium ethoxide (0.81mL, 21 wt % in ethanol, 2.2 mmol) at room temperature was obtainedN-butyl-4-[7-chloro-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(0.39 g, 59%) as a fluffy pale yellow solid. ¹H NMR (CDCl₃): δ 8.40 (d,1 H), 8.07 (d, 1 H), 7.65 (m, 2 H), 7.29 (m, 1 H), 7.15 (t, 2 H), 7.06(d, 1 H), 6.32 (d, 1 H), 5.16 (bs, 1H), 3.49 (q, 2 H), 1.71–1.41 (m, 4H), 0.99 (t, 3 H); ¹⁹F NMR (CDCl₃) δ −112.77; MS m/z 396 (M+1).

h)N-Butyl-4-[7-butyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine.

To a cold (−78° C.) solution of 9-methoxy-9-borabicyclo[3.3.1]nonane(1.1 mL, 1.0 M in hexane, 1.1 mmol) in tetrahydrofuran was addedn-butyllithium (696 μL, 1.6 M in hexane, 1.1 mmol) dropwise. Theresultant mixture was warmed to room temperature, then potassiumphosphate (371 μL, 3.0 M aqueous, 1.1 mmol) was added. A solution ofN-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(44 mg, 0.11 mmol) and[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (9 mg,complex with dichloromethane, 0.011 mmol) in N,N-dimethylformamide (1.5mL) was added to the stirring borane solution. The reaction mixture wasstirred 16 hours at room temperature. The resultant mixture was dilutedwith ethyl acetate, washed with water and brine, then dried overmagnesium sulfate. Filtration and concentration, followed by flashchromatography (4:1 hexanes:ethylacetate) provided a crude residue. To asolution of the crude residue in dioxane (10 mL) was added saturatedaqueous sodium acetate solution (1 mL) and 30% aqueous hygrogen peroxide(1 mL). After stirring at room temperature for 2 hours, the mixture wasdiluted with ethyl acetate, washed with water and brine, then dried overmagnesium sulfate. Filtration and concentration, followed by flashchromatography (59:1 dichloromethane:methanol) providedN-butyl-4-[7-butyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(7 mg, 16%). ¹H NMR (400 MHz, CDCl₃) δ 8.29 (d, 1H), 8.05 (d, 1H), 7.66(m, 2H), 7.29 (m, 1H), 7.14 (t, 2H), 6.77 (d, 1H), 6.33 (d, 1H), 5.17(br, 1H), 3.49 (m, 2H), 3.22 (t, 2H), 1.87 (m, 2H), 1.69–1.42 (m, 6H),1.02–0.97 (m, 6H); MS m/z 418 (M+1). To a solution of the product inether was added 1 M HCl in ether. The precipitated solid was isolated togive the corresponding hydrochloride salt as a pale yellow solid.

EXAMPLE 38N-Butyl-4-[2-(4fluorophenyl)-7-methylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

To a solution ofN-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(80 mg, 0.20 mmol) in tetrahydrofuran (1 mL) was added dimethylzinc (304μL, 2.0 M in toluene, 0.60 mmol) andtetrakis(triphenyl-phosphine)palladium(0) (23 mg, 0.02 mmol). Thereaction mixture was heated at 60° C. for 16 hours. The reaction mixturewas cooled, then quenched with ice water. The resultant mixture wasextracted with ethyl acetate. The organic layer was washed with waterand brine, then dried over magnesium sulfate. Filtration andconcentration, followed by flash chromatography (3:1 hexanes:ethylacetate) providedN-butyl-4-[2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(24 mg, 32%) as a yellow solid. R_(f) 0.33 (2:1 hexanes:ethyl acetate);¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, 1H), 8.04 (d, 1H), 7.64 (m, 2H), 7.27(m, 1H), 7.13 (t, 2H), 6.77 (d, 1H), 6.31 (d, 1H), 5.17 (br, 1H), 3.48(m, 2H), 2.80 (s, 3H), 1.65 (m, 2H), 1.45 (m, 2H), 0.97 (t, 3H); MS m/z376 (M+1).

EXAMPLE 39N-Butyl-4-[2-(4-fluorophenyl)-7-octylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

A mixture of 9-borabicyclo[3.3.1]nonane dimer (32 mg, 0.13 mmol) andtetrahydrofuran was stirred at room temperature for 2 hours. To theresultant solution was added 1-octene (38 μL, 0.24 mmol) and thereaction mixture was stirred 4 hours at room temperature. Potassiumphosphate (169 μL, 3 M aqueous, 0.507 mmol) was added and the reactionwas stirred for 15 minutes. A solution ofN-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(80 mg, 0.20 mmol) and[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (8 mg, 0.01mmol) in N,N-dimethylformamide was added to the borane solution andstirred 18 hours. In a separate flask, 9-borabicyclo[3.3.1]nonane dimer(32 mg, 0.13 mmol) was stirred with tetrahydrofuran for 2 hours, towhich 1-octene (38 μL, 0.24 mmol) was added and stirred 4 hours.Potassium phosphate (169 μL, 3 M aqueous, 0.507 mmol) was added and thesolution was stirred for 15 minutes. This fresh borane solution wasadded to the original reaction mixture. Additional[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (8 mg, 0.01mmol) was added and the reaction mixture was stirred 24 hours at roomtemperature. The reaction mixture was diluted with ethyl acetate. Theorganic layer was washed with water and brine, then dried over magnesiumsulfate. Filtration and concentration, followed by flash chromatography(39:1 dichloromethane:methanol) providedN-butyl-4-[2-(4-fluorophenyl)-7-octylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(8 mg, 8%). ¹H NMR (300 MHz, CD₃OD) δ 8.80–8.55 (br, 1H), 7.84 (br, 1H),7.71–7.65 (m, 3H), 7.35 (t, 2H), 7.17 (d, 1H), 6.55 (br, 1H), 3.32 (m,2H), 3.26 (t, 2H), 1.90 (m, 2H), 1.75 (m, 2H), 1.54–1.25 (m, 12H), 1.03(t, 3H), 0.89 (t, 3H); MS m/z 474 (M+1).

EXAMPLE 40N-Cyclopropyl-4-[7-ethyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

a)4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine.

In a similar manner as described in Example 37, from1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(2.65 g, 8.9 mmol) and N-cyclopropylguanidine sulfate (2.27 g, 11.5mmol) was prepared4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine(1.59 g, 47%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.66 (m, 1 H), 8.03(m, 1 H), 7.66 (m, 2 H), 7.35 (t, 1 H), 7.18 (m, 3 H), 6.40 (d, 1 H),6.06 (broad, 1 H), 2.90 (m, 1 H), 0.91 (m, 2 H), 0.70 (m, 2 H); ¹⁹F NMR(CDCl₃) δ −112.22; MS m/z 380 (M+1).

b)N-Cyclopropyl-4-[7-ethyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine.

In a similar manner as described in Example 38, from4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine(100 mg, 0.26 mmol) and diethylzinc was preparedN-cyclopropyl-4-[7-ethyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(51.6 mg, 52%) as an off-white solid. ¹H NMR (CDCl₃): δ 8.51 (m, 1 H),7.99 (m, 1 H), 7.63 (m, 2 H), 7.35 (m, 1 H), 7.16 (t, 2 H), 6.82 (d, 1H), 6.37 (d, 1 H), 3.25 (q, 2 H), 2.87 (m, 1 H), 1.45 (t, 3 H), 0.88 (m,2 H), 0.67 (m, 2 H); ¹⁹F NMR (CDCl₃) δ −113.32; MS m/z 374 (M+1).

EXAMPLE 414-[7-Butoxy-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

The title compound was prepared in a similar manner as described inabove examples to give a yellow solid. ¹H NMR (CDCl₃): δ 8.08 (d, 1H),8.02 (d, 1H), 7.59 (d, 2H), 7.30 (m, 1H), 6.97 (d, 2H), 6.34 (d, 1H),6.23 (d, 1H), 5.13 (d, 1H), 4.41–4.34 (m, 3H), 3.87 (s, 3H), 2.10 (m,2H), 1.99 (m, 2H), 1.80–1.54 (m, 8H), 1.02 (t, 3H); MS m/z458 (M+1).

EXAMPLE 424-[5-Chloro-2-(3-chlorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

The title compound was prepared in a similar manner as described inabove examples to give a yellow solid. R_(f)0.23 (4:1 hexanes:ethylacetate); ¹H NMR (CDCl₃) δ 8.37 (s, 1H), 8.02 (d, 1H), 7.70 (s, 1H),7.50 (d, 1H), 7.45–7.33 (m, 2H), 6.61 (s, 1H), 6.29 (d, 1H), 5.20 (d,1H), 4.36 (m, 1H), 2.65 (s, 3H), 2.15 (m, 2H), 1.84–1.52 (m, 6H); MS m/z470 (M+1).

EXAMPLE 43N-cyclopentyl-6-[2-(4-fluorophenyl)-7-(methylthio)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-4-amine

The title compound was prepared in a similar manner as described inabove examples to give a peach colored solid. ¹H NMR (CDCl₃) δ 8.60 (s,1H), 8.26 (d, 1H), 7.86 (m, 2H), 7.32 (t, 1H), 7.15 (t, 2H), 6.70 (d,1H), 6.08 (s, 1H), 4.95 (br, 1H), 3.58 (br, 1H), 2.65 (s, 3H), 1.85–1.50(m, 6H), 1.38–1.22 (m, 2H); MS m/z 420 (M+1).

EXAMPLE 44N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylthio)-5-morpholin-4-ylpyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine

In a similar manner as described for above examples the title compoundwas prepared as a solid. ¹H NMR (CDCl₃): δ 8.01 (d, 1H), 7.64 (m, 3H),7.15 (t, 2H), 6.45 (d, 1H), 6.26 (d, 1H), 5.17 (d, 1H), 4.46 (m, 1H),3.93 (m, 4H), 3.33 (m, 4H), 2.66 (s, 3H), 2.1–1.5 (m, 8H); ¹⁹F NMR(CDCl₃): δ −113.5; MS m/z 505 (M+1).

EXAMPLE 45N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(isopropylthio)-5-morpholin-4-ylpyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine

In a similar manner as described for above examples the title compoundwas prepared as a solid. ¹H NMR (CDCl₃): δ 8.01 (d, 1H), 7.66 (m, 3H),7.15 (t, 2H), 6.71 (d, 1H), 6.27 (d, 1H), 5.21 (d, 1H), 4.44 (m, 1H),3.93 (m, 4H), 3.31 (m, 4H), 2.1–1.5 (m, 9H), 1.44 (d, 6H); ¹⁹F NMR(CDCl₃): δ −113.6; MS m/z 534 (M+1).

EXAMPLES 46–179

Using the techniques described above for Examples 1–45, the followingadditional compounds are prepared.

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EXAMPLE 180 Biological Activity

In the following example, “MEM” means Minimal Essential Media; “FBS”means Fetal Bovine Serum; “NP40” and “Igepal” are detergents; “MOI”means Multiplicity of Infection; “NaOH” means sodium hydroxide; “MgCl₂”means magnesium chloride; “dATP” means deoxyadenosine 5′ triphosphate;“dUTP” means deoxyuridine 5′ triphosphate; “dCTP” means dexoxycytidine5′ triphosphate; “dGTP” means deoxyguanosine 5′ triphosphate; “GuSCN”means Guanidinium thiocyanate; “EDTA” means ethylenediamine tetraaceticacid; “TE” means Tris-EDTA; “SCC” means sodium chloride/sodium citrate;“APE” means a solution of ammonia acetate, ammonia phosphate, EDTA;“PBS” means phosphate buffered saline; and “HRP” means horseradishperoxidase.

a) Tissue Culture and HSV Infection.

Vero 76 cells were maintained in MEM with Earle's salts, L-glutamine, 8%FBS (Hyclone, A-1111-L) and 100 units/mL Penicillin-100 μg/mLStreptomycin. For assay conditions, FBS was reduced to 2%. Cells areseeded into 96-well tissue culture plates at a density of 5×10⁴cells/well after being incubated for 45 min at 37° C. in the presence ofHSV-1 or HSV-2 (MOI=0.001). Test compounds are added to the wells andthe plates are incubated at 37° C. for 40–48 hours. Cell lysates areprepared as follows: media was removed and replaced with 150 μL/well 0.2N NaOH with 1% Igepal CA 630 or NP-40. Plates were incubated up to 14days at room temperature in a humidified chamber to prevent evaporation.

(b) Preparation of Detection DNA.

For the detection probe, a gel-purified, digoxigenin-labeled, 710-bp PCRfragment of the HSV UL-15 sequence was utilized. PCR conditions included0.5 μM primers, 180 μM dTTP, 20 μM dUTP-digoxigenin (Boehringer Mannheim1558706), 200 μM each of dATP, dCTP, and dGTP, 1×PCR Buffer II (PerkinElmer), 2.5 mM MgCl₂, 0.025 units/μL of AmpliTaq Gold polymerase (PerkinElmer), and 5 ng of gel-purified HSV DNA per 100 μL. Extensionconditions were 10 min at 95° C., followed by 30 cycles of 95° C. for 1min, 55° C. for 30 sec. and 72° C. for 2 min. The amplification wascompleted with a 10-min incubation at 72° C. Primers were selected toamplify a 278 bp prove spanning a section of the HSV1 UL15 open readingframe (nucleotides 249–977). Single-stranded transcripts were purifiedwith Promega M13 Wizard kits. The final product was mixed 1:1 with amixture of 6 M GuSCN, 100 mM EDTA and 200 μg/mL herring sperm DNA andstored at 4° C.

(c) Preparation of Capture Plates.

The capture DNA plasmid (HSV UL13 region in pUC) was linearized bycutting with Xba I, denatured for 15 min at 95° C. and dilutedimmediately into Reacti-Bind DNA Coating Solution (Pierce, 17250,diluted 1:1 with TE buffer, pH 8) at 1 ng/μL 75 μL/well were added toCorning (#3922 or 9690) white 96-well plates and incubated at roomtemperature for at least 4 hrs before washing twice with 300 μL/well0.2×SSC/0.05% Tween-20 (SSC/T buffer). The plates were then incubatedovernight at room temperature with 150 μL/well 0.2 N NaOH, 1% IGEPAL and10 μg/mL herring sperm DNA.

(d) Hybridization.

Twenty-seven (27) μL of cell lysate was combined with 45 μL ofhybridization solution (final concentration: 3M GuSCN, 50 mM EDTA, 100μg/ml salmon sperm DNA, 5× Denhardt's solution, 0.25×APE, and 5 ng ofthe digoxigenin-labeled detection probe). APE is 1.5 M NH₄-acetate, 0.15M ammonium phosphate monobasic, and 5 mM EDTA adjusted to pH 6.0.Mineral oil (50 μL) was added to prevent evaporation. The hybridizationplates were incubated at 95° C. for 10 minutes to denature the DNA, thenincubated at 42° C. overnight. The wells were washed 6× with 300 μL/wellSSC/T buffer then incubated with 75 μL/wellanti-digoxigenin-HRP-conjugated antibody (Boehringer Mannheim 1207733,1:5000 in TE) for 30 min at room temperature. The wells were washed 6×with 300 μL/well with PBS/0.05% Tween-20 before 75 μL/well SuperSignalLBA substrate (Pierce) was added. The plates were incubated at roomtemperature for 30 minutes and chemiluminescence was measured in aWallac Victor reader.

e) Results.

The following results were obtained for HSV-1.

Example No. IC₅₀ (μM) 9 2.5 11 10 12 5 14 2 16 0.9 18 25 19 15 20 15 2315 32 2 36 1 37 0.6 38 1 39 6 40 3 41 0.28 42 1.0 43 1.3 44 0.5 45 0.9

The results demonstrated that the compounds of the present invention areuseful for The treatment and prophylaxis of herpes viral infections.

1. A compound of formula (I):

wherein: R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het,—OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay,—R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het, —R¹⁰OC(O)R⁹, —R¹⁰OC(O)Ay,—R¹⁰OC(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay,—R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,—C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰OS(O)_(n)R⁹, —R¹⁰NHSO₂R⁹,—R¹⁰NHCOR⁹, —S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, cyano, azido andnitro; each R⁷ and R⁸ are the same or different and are independentlyselected from the group consisting of H, alkyl, cycloalkyl, alkenyl,cycloalkenyl, —R¹⁰cycloalkyl, —OR⁹, —R¹⁰OR⁹, —R¹⁰NR⁹R¹¹, —R¹⁰C(O)R⁹,—C(O)R⁹, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁹R¹¹, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹,—R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —R¹⁰C(NH)NR⁹R¹¹, —C(NH)NR⁹R¹¹,—SO₂NR⁹R¹¹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰NHSO₂R⁹, —SO₂R¹⁰, —R¹⁰SO₂R¹⁰, —R¹⁰NHCOR⁹and —R¹⁰SO₂NHCOR⁹; each R⁹ and R¹¹ are the same or different and areindependently selected from the group consisting of H, alkyl,cycloalkyl, —R¹⁰cycloalkyl, —R¹⁰OH, —R¹⁰(OR¹⁰)w where w is 1–10, and—R¹⁰NR¹⁰R¹⁰; each R¹⁰ is the same or different and is independentlyselected from the group consisting of alkyl, cycloalkyl, alkenyl,cycloalkenyl and alkynyl; Ay is an aryl; Het is a 5- or 6-memberedheterocyclic or heteroaryl group; n is 0, 1 or 2; R² is selected fromthe group consisting of H, halo, alkyl, cycloalkyl, alkenyl,cycloalkenyl, —NR⁷R⁸, Ay, —NHR¹⁰Ay, —OR⁷, —OAy, —S(O)_(n)R⁹,—S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet and—OR¹⁰Het; Y is N; R³ and R⁴ are the same or different and are eachindependently selected from the group consisting of H, halo, alkyl,cycloalkyl, alkenyl, Ay, —OR⁷, —OAy, —R¹⁰OR⁷, —R¹⁰OAy, —NR⁷R⁸, —NR⁷Ay,—R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹, Het,—NHHet and —NHR¹⁰Het; q is 0, 1, 2, 3, 4 or 5; each R⁵ is the same ordifferent and is independently selected from the group consisting ofhalo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl,Ay, —NHR¹⁰Ay, —NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OR⁷, —OAy, —OHet,—R¹⁰OR⁹, —NR⁷R⁸, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay,—C(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het,—R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,—C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, azido andnitro; or two adjacent R⁵ groups together with the atoms to which theyare bonded form a C₅₋₆ cycloalkyl or aryl; p is 0, 1, 2 or 3; and eachR⁶ is the same or different and is independently selected from the groupconsisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,—R¹⁰cycloalkyl, Ay, Het, —R¹⁰Ay, —R¹⁰Het, —OR⁷, —OAy, —OHet, —R¹⁰OR⁹,—OR¹⁰Ay, —OR¹⁰Het, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay,—C(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het,—R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹,—C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay,—R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —S(O)_(n)R⁹, cyano, azido andnitro; or two adjacent R⁶ groups together with the atoms to which theyare bonded form a C₅₋₆ cycloalkyl or a 5- or 6-membered heterocyclicgroup containing 1 or 2 heteroatoms; wherein when Y is CH, R³ is not—NR⁷Ay; or a pharmaceutically acceptable salt or solvate thereof.
 2. Thecompound according to claim 1 wherein R¹ is selected from the groupconsisting of alkyl, cycloalkyl, —R¹⁰cycloalkyl, —OR⁷, —OAy, —R¹⁰OR⁹,—R¹⁰NR⁷R⁸, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —S(O)₂NR⁷R⁸, —S(O)_(n)R⁹, cyano,nitro and azido.
 3. The compound according to claim 1 wherein R¹ isselected from the group consisting of alkyl, —OR⁷, —C(O)NR⁷R⁸ and—S(O)_(n)R⁹.
 4. The compound according to claim 1 wherein R² is selectedfrom the group consisting of —NR⁷R⁸, —OR⁷, —S(O)_(n)R⁹, Het, —NHHet and—NHR¹⁰Het.
 5. The compound according to claim 1 wherein R² is —NR⁷R⁸ orHet.
 6. The compound according to claim 1 wherein R³ and R⁴ are the sameor different and are each independently selected from the groupconsisting of H, halo, alkyl, Ay, —OR⁷, —R¹⁰OR⁷, —NR⁷R⁸, —R¹⁰NR⁷R⁸ and—CO₂R⁷.
 7. The compound according to claim 1 wherein R³ and R⁴ are bothH.
 8. The compound according to claim 1 wherein q is 0, 1 or
 2. 9. Thecompound according to claim 1 wherein each R⁵ is the same or differentand is independently selected from the group consisting of halo, alkyl,alkenyl, Ay, —OR⁷, —OAy, —NR⁷R⁸, —NR⁷Ay, —NHR¹⁰Ay, Het, —CO₂R⁹,—C(O)NR⁷R⁸, —C(O)NR⁷Ay, —S(O)₂NR⁷R⁸, cyano, nitro and azido.
 10. Thecompound according to claim 1, wherein each R⁵ is the same or differentand is independently selected from the group consisting of halo, alkyl,—OR⁷, —NR⁷R⁸ and cyano.
 11. The compound according to claim 1, wherein pis 0 or
 1. 12. The compound according to claim 1 wherein each R⁶ is thesame or different and is independently selected from the groupconsisting of halo, alkyl, Ay, Het, —OR⁷, —OAy, —OHet, —R¹⁰OR⁹,—R¹⁰NR⁷R⁸, —C(O)R⁹, —CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Het,—R¹⁰C(O)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —R¹⁰SO₂NHCOR⁹, —S(O)_(n)R⁹, cyano, azidoand nitro.
 13. The compound according to claim 1, wherein each R⁶ is thesame or different and is independently selected from the groupconsisting of halo, alkyl, Het, —OR⁷, —C(O)NR⁷R⁸, —S(O)₂NR⁷R⁸,—S(O)_(n)R⁹ and cyano.
 14. A compound selected from the group consistingof:2-(4-Fluorophenyl)-7-methyl-3-(4-pyrimidinyl)pyrazolo[1,5-a]pyridine;2-(4-Fluorophenyl)-7-methylthio-3-(4-pyrimidinyl)pyrazolo[1,5-a]pyridine;2-(4-Fluorophenyl)-7-methylsulfinyl-3-(4-pyrimidinyl)pyrazolo[1,5-a]-pyridine;7-(2-Fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-pyrazolo[1,5-a]pyridine;N-Butyl-4-[7-(2-fluoroethoxy)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;N-Benzyl-4-[7-(2-fluoroethoxy)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;2-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine;N-Butyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;N-Benzyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]-pyridin-3-yl]-2-pyrimidinamine;N-Cyclopropyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;N-Cyclohexyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;3-(4-[2-(4-Fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinylamino)-1-propanol;2-(4-Fluorophenyl)-3-(4-(2-methyloxy)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine;2-(4-Fluorophenyl)-3-(4-(2-phenyloxy)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine;2-(4-Fluorophenyl)-3-(4-(2-(2,2,2-trifluoroethoxy))pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine;2-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(ethylsulfinyl)pyrazolo[1,5-a]pyridine;2-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-7-(ethylthio)pyrazolo[1,5-a]pyridine;Dimethyl2-(4-fluorophenyl)-3-(4-(2-cyclopropylamino)pyrimidinyl)-7-pyrazolo[1,5-a]pyridinylcarboxamide;7-(2-Fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-pyrazolo[1,5-a]pyridine;2-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)-pyrazolo[1,5-a]pyridine;N-{4-[5-Chloro-7-(ethylsulfanyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamineEthyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylate;3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylicacid;3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxamide;N-Butyl-4-[7-butyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;N-Butyl-4-[2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;N-Butyl-4-[2-(4-fluorophenyl)-7-octylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;N-Cyclopropyl-4-[7-ethyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;4-[7-Butoxy-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine;4-[5-Chloro-2-(3-chlorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine;N-cyclopentyl-6-[2-(4-fluorophenyl)-7-(methylthio)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-4-amine;N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylthio)-5-morpholin-4-ylpyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine;andN-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(isopropylthio)-5-morpholin-4-ylpyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine;and pharmaceutically acceptable salts and solvates thereof.
 15. Apharmaceutical composition comprising a compound according to claim 1.16. The pharmaceutical composition according to claim 15, furthercomprising a pharmaceutically acceptable carrier or diluent.
 17. Thepharmaceutical composition according to claim 15 further comprising anantiviral agent selected from the group consisting of aciclovir andvalaciclovir.
 18. A process for preparing a compound according to claim1, wherein Y is N; R² is selected from the group consisting of H, alkyl,cycloalkyl, alkenyl, cycloalkenyl, —NR⁷R⁸, Ay, —NHR¹⁰Ay, —OR⁷, —OAy,—S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het,—OHet, and —OR¹⁰Het; R³ is H and R⁴ is H, said process comprising thesteps of: a) reacting a compound of formula (IX):

wherein R^(1a) is selected from the group consisting of H, halo, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het, —R¹⁰OC(O)R⁹,—R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay,—C(O)NHR¹⁰Ay, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —R¹⁰C(NH)NR⁹R¹¹,—S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹⁰, —R¹¹SO₂R⁹,—R¹⁰OS(O)_(n)R⁹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹, —S(O)_(n)R⁹, —S(O)_(n)Ay,—S(O)_(n)Het, cyano, azido and nitro;  with a compound of formula (X):

 to prepare a compound of formula (XI):

 and b) when R^(1a) is H or halo, converting the compound of formula(XI), to a compound of formula (I).
 19. A process for preparing acompound according to claim 1 wherein Y is N; R² is selected from thegroup consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, —NR⁷R⁸,Ay, —NHR¹⁰Ay, —OR⁷, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het; R³ is selectedfrom the group consisting of H, alkyl, cycloalkyl, alkenyl, Ay, —R¹⁰OR⁷,—R¹⁰OAy, —NR⁷R⁸ where R⁷ and R⁸ are not H, —NR⁷Ay where R⁷ is not H,—R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —C(O)R⁷, —C(O)Ay, —CO₂R⁷, —CO₂Ay, —SO₂NHR⁹ andHet; and R⁴ is H; said process comprising the steps of: a) reacting acompound of formula (XV):

wherein R^(1a) is selected from the group consisting of H, halo, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het, —R¹⁰OC(O)R⁹,—R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay,—C(O)NHR¹⁰Ay, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —R¹⁰C(NH)NR⁹R¹¹,—S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹,—R¹⁰OS(O)_(n)R⁹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹, —S(O)_(n)R⁹, —S(O)_(n)Ay,—S(O)_(n)Het, cyano, azido and nitro;  with a compound of formula (X):

 to prepare a compound of formula (XI):

 and b) when R^(1a) is H or halo, converting the compound of formula(XI) to a compound of formula (I).
 20. A process for preparing acompound according to claim 1, wherein Y is N and R² is selected fromthe group consisting of H, alkyl, cycloalkyl, alkenyl, cycloalkenyl,—NR⁷R⁸, Ay, —NHR¹⁰Ay, —OR⁷, —OAy, —S(O)_(n)R⁹, —S(O)_(n)Ay, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, Het, —NHHet, —NHR¹⁰Het, —OHet, and —OR¹⁰Het, said processcomprising the steps of: a) reacting a compound of formula (XVIII):

wherein R^(1a) is selected from the group consisting of H, halo, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰Ay,—R¹⁰Het, —OR⁷, —OAy, —OHet, —OR¹⁰Ay, —OR¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸,—R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —C(O)R⁹, —C(O)Ay, —C(O)Het, —R¹⁰OC(O)R⁹,—R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —CO₂R⁹, —R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay,—C(O)NHR¹⁰Ay, —R¹⁰C(O)NR⁹R¹¹, —C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹,—R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸, —C(NH)NR⁷Ay, —R¹⁰C(NH)NR⁹R¹¹,—S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹, —R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹,—R¹⁰OS(O)_(n)R⁹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹, —S(O)_(n)R⁹, —S(O)_(n)Ay,—S(O)_(n)Het, cyano, azido and nitro;  with a compound of formula (X):

 followed by oxidative aromatization, to prepare a compound of formula(XI):

 and b) when R^(1a) is H or halo, converting the compound of formula(XI) to a compound of formula (I).
 21. A process for preparing acompound according to claim 1, said process comprising the steps of: a)reacting a compound of formula (XIX):

wherein X¹ is halo; and wherein R^(1a) is selected from the groupconsisting of H, halo, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, —R¹⁰cycloalkyl, —R¹⁰Ay, —R¹⁰Het, —OR⁷, —OAy, —OHet,—OR¹⁰Ay, —OR¹⁰Het, —R¹⁰OR⁹, —R¹⁰NR⁷R⁸, —R¹⁰NR⁷Ay, —R¹⁰C(O)R⁹, —C(O)R⁹,—C(O)Ay, —C(O)Het, —R¹⁰OC(O)R⁹, —R¹⁰OC(O)Ay, —R¹⁰OC(O)Het, —CO₂R⁹,—R¹⁰CO₂R⁹, —C(O)NR⁷R⁸, —C(O)NR⁷Ay, —C(O)NHR¹⁰Ay, —R¹⁰C(O)NR⁹R¹¹,—C(S)NR⁹R¹¹, —R¹⁰C(S)NR⁹R¹¹, —R¹⁰NHC(NH)NR⁹R¹¹, —C(NH)NR⁷R⁸,—C(NH)NR⁷Ay, —R¹⁰C(NH)NR⁹R¹¹, —S(O)₂NR⁷R⁸, —S(O)₂NR⁷Ay, —R¹⁰SO₂NHCOR⁹,—R¹⁰SO₂NR⁹R¹¹, —R¹⁰SO₂R⁹, —R¹⁰OS(O)_(n)R⁹, —R¹⁰NHSO₂R⁹, —R¹⁰NHCOR⁹,—S(O)_(n)R⁹, —S(O)_(n)Ay, —S(O)_(n)Het, cyano, azido and nitro;  with acompound of formula (XX)

wherein M² is selected from the group consisting of —B(OH)₂, —B(ORa)₂,—B(Ra)₂, —Sn(Ra)₃, Zn-halide, ZnRa, Mg-halide where Ra is alkyl orcycloalkyl and halide is halo;  to prepare a compound of formula (XI):

 and b) when R^(1a) is H or halo, converting the compound of formula(XI), to a compound of formula (I).
 22. The process according to claim18 further comprising the step of converting a compound of formula (XI)to a pharmaceutically acceptable salt or solvate thereof.
 23. Theprocess according to claim 22 further comprising the step of convertinga compound of formula (XI) or a pharmaceutically acceptable salt orsolvate thereof to another compound of formula (XI) or apharmaceutically acceptable salt or solvate thereof.
 24. The processaccording to claim 18 further comprising the step of converting acompound of formula (I) to a pharmaceutically acceptable salt or solvatethereof.
 25. The process according to claim 18 further comprising thestep of converting a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof to another compound of formula (I) ora pharmaceutically acceptable salt or solvate thereof.